Alkyne compounds for treatment of complement mediated disorders

ABSTRACT

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R 12  or R 13  on the A group is an alkyne (R 32 ) are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D&#39;s ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/818,559, filed Nov. 20, 2017, which is a continuation of U.S.application Ser. No. 14/631,090, filed Feb. 25, 2015, now U.S. Pat. No.9,828,396, which claims the benefit of provisional U.S. Application No.61/944,189, filed Feb. 25, 2014, provisional U.S. Application No.62/022,916, filed Jul. 10, 2014, and provisional U.S. Application62/046,783, filed Sep. 5, 2014. The entirety of each of theseapplications is hereby incorporated by reference for all purposes.

BACKGROUND

The complement system is a part of the innate immune system which doesnot adapt to changes over the course of the host's life, but isrecruited and used by the adaptive immune system. For example, itassists, or complements, the ability of antibodies and phagocytic cellsto clear pathogens. This sophisticated regulatory pathway allows rapidreaction to pathogenic organisms while protecting host cells fromdestruction. Over thirty proteins and protein fragments make up thecomplement system. These proteins act through opsonization (enhancingphaogytosis of antigens), chemotaxis (attracting macrophages andneutrophils), cell lysis (rupturing membranes of foreign cells) andagglutination (clustering and binding of pathogens together).

The complement system has three pathways: classical, alternative andlectin. Complement factor D plays an early and central role inactivation of the alternative pathway of the complement cascade.Activation of the alternative complement pathway is initiated byspontaneous hydrolysis of a thioester bond within C3 to produce C3(H₂O),which associates with factor B to form the C3(H₂O)B complex. Complementfactor D acts to cleave factor B within the C3(H₂O)B complex to form Baand Bb. The Bb fragment remains associated with C3(H₂O) to form thealternative pathway C3 convertase C3(H₂O)Bb. Additionally, C3b generatedby any of the C3 convertases also associates with factor B to form C3bB,which factor D cleaves to generate the later stage alternative pathwayC3 convertase C3bBb. This latter form of the alternative pathway C3convertase may provide important downstream amplification within allthree of the defined complement pathways, leading ultimately to therecruitment and assembly of additional factors in the complement cascadepathway, including the cleavage of C5 to C5a and C5b. C5b acts in theassembly of factors C6, C7, C8, and C9 into the membrane attack complex,which can destroy pathogenic cells by lysing the cell.

The dysfunction of or excessive activation of complement has been linkedto certain autoimmune, inflammatory, and neurodegenerative diseases, aswell as ischemia-reperfusion injury and cancer. For example, activationof the alternative pathway of the complement cascade contributes to theproduction of C3a and C5a, both potent anaphylatoxins, which also haveroles in a number of inflammatory disorders. Therefore, in someinstances, it is desirable to decrease the response of the complementpathway, including the alternative complement pathway. Some examples ofdisorders mediated by the complement pathway include age-related maculardegeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiplesclerosis, and rheumatoid arthritis.

Age-related macular degeneration (AMD) is a leading cause of vision lossin industrialized countries. Based on a number of genetic studies, thereis evidence of the link between the complement cascade and maculardegeneration. Individuals with mutations in the gene encoding complementfactor H have a fivefold increased risk of macular degeneration andindividuals with mutations in other complement factor genes also have anincreased risk of AMD. Individuals with mutant factor H also haveincreased levels of C-reactive protein, a marker of inflammation.Without adequate functioning factor H, the alternative pathway of thecomplement cascade is overly activated leading to cellular damage.Inhibition of the alternative pathway is thus desired.

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant,hematological disorder characterized by the expansion of hematopoieticstem cells and progeny mature blood cells which are deficient in somesurface proteins. PNH erythrocytes are not capable of modulating theirsurface complement activation, which leads to the typical hallmark ofPNH—the chronic activation of complement mediated intravascular anemia.Currently, only one product, the anti-C5 monoclonal antibody eculizumab,has been approved in the U.S. for treatment of PNH. However, many of thepatients treated with eculizumab remain anemic, and many patientscontinue to require blood transfusions. In addition, treatment witheculizumab requires life-long intravenous injections. Thus, there is anunmet need to develop novel inhibitors of the complement pathway.

Factor D is an attractive target for inhibition or regulation of thecomplement cascade due to its early and essential role in thealternative complement pathway, and its potential role in signalamplification within the classical and lectin complement pathways.Inhibition of factor D effectively interrupts the pathway and attenuatesthe formation of the membrane attack complex.

While initial attempts have been made to develop inhibitors of factor D,there are currently no small molecule factor D inhibitors in clinicaltrials. Examples of factor D inhibitors or prolyl compounds aredescribed in the following disclosures.

Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled “Compoundsuseful in the complement, coagulat and kallikrein pathways and methodfor their preparation” describes fused bicyclic ring compounds that arepotent inhibitors of factor D. Development of the factor D inhibitorBCX1470 was discontinued due to lack of specificity and short half-lifeof the compound.

Novartis PCT patent publication WO2012/093101 titled “Indole compoundsor analogues thereof useful for the treatment of age-related maculardegeneration” describes certain factor D inhibitors.

Novartis PCT patent publications WO2014/002057 titled “Pyrrolidinederivatives and their use as complement pathway modulators” andWO2014/009833 titled “Complement pathway modulators and uses thereof”describe additional factor D inhibitors with heterocyclic substituents.Additional factor D inhibitors are described in Novartis PCT patentpublications WO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054,WO2014/002058, WO2014/002059, and WO2014/005150.

Bristol-Myers Squibb PCT patent publication WO2004/045518 titled “Openchain prolyl urea-related modulators of androgen receptor function”describes open chain prolyl urea and thiourea related compounds for thetreatment of androgen receptor-associated conditions, such asage-related diseases, for example, sarcopenia.

Japan Tobacco Inc. PCT patent publication WO1999/048492 titled “Amidederivatives and nociceptin antagonists” describes compounds with aproline-like core and aromatic substituents connected to the prolinecore through amide linkages useful for the treatment of pain.

Ferring B. V. and Yamanouchi Pharmaceutical Co. lTD. PCT patentpublication WO1993/020099 titled “CCK and/or gastrin receptor ligands”describes compounds with a proline-like core and heterocyclicsubstituents connected to the proline core through amide linkages forthe treatment of, for example, gastric disorders or pain.

Alexion Pharmaceuticals PCT patent publication WO1995/029697 titled“Methods and compositions for the treatment of glomerulonephritis andother inflammatory diseases” discloses antibodies directed to C5 of thecomplement pathway for the treatment of glomerulonephritis andinflammatory conditions involving pathologic activation of thecomplement system. Alexion Pharmaceutical's anti-C5 antibody eculizumab(Soliris®) is currently the only complement-specific antibody on themarket, and is the first and only approved treatment for paroxysmalnocturnal hemoglobinuria (PNH).

Compounds which mediate the complement pathway, and for example, act asfactor D inhibitors are needed for treatment of disorders in a host,including a human, associated with misregulation of the complementcascade.

SUMMARY

It has been discovered that a compound of Formula I, or apharmaceutically acceptable salt or composition thereof, wherein R¹² orR¹³ on the A group is an alkyne (R³²), is a superior inhibitor ofcomplement factor D. In one embodiment, the alkyne is directly linked tothe A group. In another embodiment, the alkyne is indirectly linked tothe A group through a linking moiety, defined further below.

In one embodiment, a method for the treatment of a disorder associatedwith a dysfunction, including increased activity, of the complementpathway is provided that includes the administration of an effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof, optionally in a pharmaceutically acceptable carrier, asdescribed in more detail below.

In one embodiment, the disorder is associated with the alternativecomplement cascade pathway. In yet another embodiment, the disorder isassociated with the complement classical pathway. In a furtherembodiment, the disorder is associated with the complement lectinpathway. The factor D inhibitors provided herein can thus dampen orinhibit detrimental complement activity in a host, by administration ofan effective amount in a suitable manner to a host in need thereof.

Specific embodiments of this invention are directed to certain diseaseindications. In one embodiment, a method for the treatment of paroxysmalnocturnal hemoglobinuria (PNH) is provided that includes theadministration of an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In another embodiment, a method forthe treatment of age-related macular degeneration (AMD) is provided thatincludes the administration of an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, optionally ina pharmaceutically acceptable carrier. In another embodiment, a methodfor the treatment of rheumatoid arthritis is provided that includes theadministration of an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In another embodiment, a method forthe treatment of multiple sclerosis is provided that includes theadministration of an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In other embodiments of the invention, an active compound providedherein can be used to treat or prevent a disorder in a host mediated bycomplement factor D, or by an excessive or detrimental amount of the C3amplification loop of the complement pathway. As examples, the inventionincludes methods to treat or prevent complement associated disordersthat are induced by antibody-antigen interactions, a component of animmune or autoimmune disorder or by ischemic injury. The invention alsoprovides methods to decrease inflammation or an immune response,including an autoimmune response, where mediated or affected by factorD.

The disclosure provides compounds of Formula I

and the pharmaceutically acceptable salts and compositions thereof,wherein:

Q¹ is N(R¹) or C(R¹R^(1′));

Q² is C(R²R^(2′)), C(R²R^(2′))—C(R²R^(2′)), S, O, N(R²) or C(R²R^(2′))O;

Q³ is N(R³), S, or C(R³R^(3′));

X¹ and X² are independently N, CH, or CZ, or X¹ and X² together are C═C;and

wherein Q¹, Q², Q³, X¹, and X² are selected such that a stable compoundresults.

Non-limiting examples of the

ring are illustrated below (any of which can be otherwise substitutedwith R¹, R^(1′), R², R^(2′), R³, and R^(3′)) as described in more detailbelow.

wherein q is 0, 1, 2 or 3 and r is 1, 2 or 3.

R and R′ are independently chosen from H, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl wherein each group can be optionallysubstituted or any other substituent group herein that provides thedesired properties. In some embodiments, the ring includes one or morechiral carbon atoms. The invention includes embodiments in which thechiral carbon can be provided as an enantiomer, or mixtures ofenantiomers, including a racemic mixture. Where the ring includes morethan one stereocenter, all of the enantiomers and diastereomers areincluded in the invention as individual species.

Z is F, Cl, NH₂, CH₃, CH₂D, CHD₂, or CD₃.

R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently chosen at eachoccurrence, as appropriate, and only where a stable compound results,from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkynyl, C₂-C₆alkanoyl,C₁-C₆thioalkyl, hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)OR⁹, —OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰,—NR⁹C(O)OR¹⁰, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, where R⁹ and R¹⁰ areindependently chosen at each occurrence from hydrogen, C₁-C₆alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), and—O—C₀-C₄alkyl(C₃-C₇cycloalkyl).

In alternative embodiments, R¹ and R^(1′) or R³ and R^(3′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring or a 3- to6-membered heterocyclic spiro ring containing 1 or 2 heteroatomsindependently chosen from N, O, or S; R² and R^(2′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring; or R² andR^(2′) may be taken together to form a 3- to 6-membered heterocyclicspiro ring; each of which spiro ring each of which ring may beunsubstituted or substituted with 1 or more substituents independentlychosen from halogen (and in particular F), hydroxyl, cyano, —COOH,C₁-C₄alkyl (including in particular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In alternative embodiments, R¹ and R² may be taken together to form a3-membered carbocyclic ring; R¹ and R² may be taken together to form a4- to 6-membered carbocyclic or aryl ring or a 4- to 6-memberedheterocyclic or heteroaryl ring containing 1 or 2 heteroatomsindependently chosen from N, O, and S; or R² and R³, if bound toadjacent carbon atoms, may be taken together to form a 3- to 6-memberedcarbocyclic or aryl ring or a 3- to 6-membered heterocyclic orheteroaryl ring; each of which ring may be unsubstituted or substitutedwith 1 or more substituents independently chosen from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In alternative embodiments, R¹ and R^(1′), R² and R^(2′), or R³ andR^(3′) can be taken together to form a carbonyl group. In alternativeembodiments, R¹ and R² or R² and R³ can be taken together to form acarbon-carbon double bond.

A is a group chosen from:

R⁴ is chosen from —CHO, —CONH₂, C₂-C₆alkanoyl, hydrogen, —SO₂NH₂,—C(CH₂)₂F, —CH(CF₃)NH₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),

each of which R⁴ other than hydrogen, —CHO, and —CONH₂, is unsubstitutedor substituted with one or more of amino, imino, halogen, hydroxyl,cyano, cyanoimino, C₁-C₂alkyl, C₁-C₂alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R⁵ and R⁶ are independently chosen from —CHO, —C(O)NH₂, —C(O)NH(CH₃),C₂-C₆alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH,—SO₂NH₂, vinyl, C₁-C₆alkyl (including methyl), C₂-C₆alkenyl,C₁-C₆alkoxy, —C₀-C₄alkyl(C₃-C₇cycloalkyl),P—C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl), —P(O)(OR⁹)₂, —OC(O)R⁹, —C(O)OR⁹,—C(O)N(CH₂CH₂R⁹)(R¹⁰), —NR⁹C(O)R¹⁰, phenyl, or 5- to 6-memberedheteroaryl.

Each R⁵ of and R⁶ other than hydrogen, hydroxyl, cyano, and —COOH isunsubstituted or optionally substituted. For example, R⁵ and R⁶ otherthan hydrogen, hydroxyl, cyano, and COOH may be substituted with one ormore substituents independently chosen from halogen, hydroxyl, amino,imino, cyano, cyanoimino, C₁-C₂alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R^(6′) is hydrogen, halogen, hydroxyl, C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), or C₁-C₄alkoxy; or R⁶ and R^(6′) may betaken together to form an oxo, vinyl, or imino group.

R⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl).

R⁸ and R^(8′) are independently chosen from hydrogen, halogen, hydroxyl,C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) can be taken together with the carbonthat they are bonded to form a 3-membered carbocyclic ring.

R¹⁶ is absent or may include one or more substituents independentlychosen from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino),—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R¹⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,—SO₂C₁-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(C₃-C₇heterocycloalkyl),—C₀-C₄alkyl(aryl), C₀-C₄alkyl(heteroaryl), and wherein R¹⁹ other thanhydrogen is unsubstituted or substituted with one or more substituentsindependently chosen from halogen, hydroxyl, amino, —COOH, and—C(O)OC₁-C₄alkyl.

X¹¹ is N or CR¹¹.

X¹² is N or CR¹².

X¹³ is N or CR¹³.

X¹⁴ is N or CR¹⁴.

No more than 2 of X¹¹, X¹², X¹³, and X¹⁴ are N.

One of R¹² and R¹³ is chosen from R³¹ and the other of R¹² and R¹³ ischosen from R³²:

R³¹ is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino,—COOH, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₂-C₆alkenyloxy, —C(O)OR⁹, C₁-C₆thioalkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and —C(NR⁹)NR⁹R¹⁰, each ofwhich R³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy is unsubstituted or substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, amino, —COOH, —CONH₂ C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,and each of which R³¹ is also optionally substituted with onesubstituent chosen from phenyl and 4- to 7-membered heterocyclecontaining 1, 2, or 3 heteroatoms independently chosen from N, O, and S;which phenyl or 4- to 7-membered heterocycle is unsubstituted orsubstituted with one or more substituents independently chosen fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl)(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, andC₁-C₂haloalkoxy;

R³² is —C₂-C₆alkynylR³⁰, and each R³² can be optionally substituted.Examples of R³² include, for example, but are not limited to,

In an alternative embodiment, R¹² and R¹³ are each independentlyselected from an R³² moiety.

R¹¹, R¹⁴, and R¹⁵ are independently chosen at each occurrence fromhydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₂-C₆alkenyl(aryl),C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), C₂-C₆alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R²¹ and R²² are independently chosen at each occurrence from hydrogen,hydroxyl, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S, and each R²¹ and R²² can be optionallysubstituted.

R²³ is independently chosen at each occurrence from C₁-C₆alkyl,C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(phenyl)C₀-C₄alkyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkyl having1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or6-membered unsaturated or aromatic heterocycle)C₀-C₄alkyl having 1, 2,or 3 heteroatoms independently chosen from N, O, and S, and each R²³ canbe optionally substituted.

R²⁴ and R²⁵ are taken together with the nitrogen to which they areattached to form a 4- to 7-membered monocyclic heterocycloalkyl group,or a 6- to 10-membered bicyclic heterocyclic group having fused, spiro,or bridged rings, and each R²⁴ and R²⁵ can be optionally substituted.

R³⁰ is independently chosen at each occurrence from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S; (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S; COOH, Si(CH₃)₃, COOR^(30a), C₂-C₆alkanoyl,—B(OH)₂, —C(O)(CH₂)₁₋₄S(O)R²¹, —P(O)(OR²¹)(OR²²), —P(O)(OR²¹)R²²,—P(O)R²¹R²², —NR⁹P(O)(NHR²¹)(NHR²²), —NR⁹P(o)(OR²¹)(NHR²²),—NR⁹P(O)(OR²¹)(OR²²), —C(S)R²¹, —NR²¹SO₂R²², —NR⁹S(O)NR¹⁰R²²,—NR⁹SO₂NR¹⁰R²², —SO₂NR⁹COR²², —SO₂NR⁹CONR²¹R²², —NR²¹SO₂R²²,—C(O)NR²¹SO₂R²², —C(NH₂)NR⁹R²², —C(NH₂)NR⁹S(O)₂R²², —NR⁹C(O)OR¹⁰,—NR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², —C(O)R²⁴R²⁵, —NR⁹C(O)R²¹, —C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR²⁴R²⁵, —(CH₂)₁₋₄OC(O)R²¹, each of which R³⁰can be optionally substituted.

R^(30a) is C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl-, (aryl)C₀-C₄alkyl-, (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl- having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S, each of which R^(30a) can be optionallysubstituted.

L is a bond or is chosen from the formulas

where R¹⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl) andR¹⁸ and R^(18′) are independently chosen from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.

B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicycliccarbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclicgroup having 1, 2, 3, or 4 heteroatoms independently selected from N, O,and S and from 4 to 7 ring atoms per ring; C₂-C₆alkenyl; C₂-C₆alkynyl;—(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); or—(C₀-C₄alkyl)(biphenyl).

Each of which B is unsubstituted or substituted with one or moresubstituents independently chosen from R³³ and R³⁴, and 0 or 1substituents chosen from R³⁵ and R³⁶.

R³³ is independently chosen from halogen, hydroxyl, —COOH, cyano,C₁-C₆alkyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R³⁴ is independently chosen from nitro, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹⁾R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(o)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰R²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)NR²², -JC(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JC(O)R²⁴R²⁵,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄OC(O)R²¹,and -JC(O)OR²³; each of which R³⁴ may be unsubstituted or substitutedwith one or more substituents independently chosen from halogen,hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂,—P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy,—C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

R³⁵ is independently chosen from naphthyl, naphthyloxy, indanyl, (4- to7-membered heterocycloalkyl)C₀-C₄alkyl containing 1 or 2 heteroatomschosen from N, O, and S, and bicyclic heterocycle containing 1, 2, or 3heteroatoms independently chosen from N, O, and S, and containing 4- to7-ring atoms in each ring; each of which R³⁵ is unsubstituted orsubstituted with one or more substituents independently chosen fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.

R³⁶ is independently chosen from tetrazolyl, (phenyl)C₀-C₂alkyl,(phenyl)C₁-C₂alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing1, 2, or 3 heteroatoms independently chosen from N, O, B, and S, each ofwhich R³⁶ is unsubstituted or substituted with one or more substituentsindependently chosen from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, —OSi(CH₃)₂C(CH₃)₃,—Si(CH₃)₂C(CH₃)₃, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

J is independently chosen at each occurrence from a covalent bond,C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, and C₂-C₄alkynylene.

Pharmaceutical compositions comprising a compound or salt of Formula Itogether with a pharmaceutically acceptable carrier are also disclosed.

Methods of treating or preventing disorders mediated by complementcascade factor D, including but not limited to age-related maculardegeneration (AMD), retinal degeneration, other ophthalmic diseases(e.g., geographic atrophy), paroxysymal nocturnal hemoglobinuria (PNH),multiple sclerosis (MS), arthritis including rheumatoid arthritis (RA),a respiratory disease or a cardiovascular disease, are provided,comprising administering a therapeutically effective amount of acompound or salt of Formula I to a host, including a human, in need ofsuch treatment are also disclosed.

In another embodiment, an effective amount of an active factor Dinhibiting compound is provided to treat an inflammatory or immunedisorder, including an autoimmune disorder, that is mediated or affectedby factor D. In an alternative embodiment, the compound of Formula I canbe used to treat a disorder mediated by the complement pathway,regardless whether it is acting through Factor D.

The present invention includes at least the following features:

(a) a compound of Formula I as described herein, and pharmaceuticallyacceptable salts and prodrugs thereof (each of which and all subgenusesand species thereof considered individually and specifically described);

(b) Formula I as described herein, and pharmaceutically acceptable saltsand prodrugs thereof, for use in treating or preventing disordersmediated by the complement pathway, and for example, cascade factor D,including age-related macular degeneration (AMD), retinal degeneration,paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), andrheumatoid arthritis (RA) and other disorders described further herein;

(c) use of Formula I, and pharmaceutically acceptable salts and prodrugsthereof in the manufacture of a medicament for use in treating orpreventing disorders mediated by complement cascade factor D, includingage-related macular degeneration (AMD), retinal degeneration,paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), andrheumatoid arthritis (RA) and other disorders described further herein;

(d) a process for manufacturing a medicament intended for thetherapeutic use for treating or preventing treating or preventingdisorders mediated by complement cascade factor D, including age-relatedmacular degeneration (AMD), retinal degeneration, paroxysymal nocturnalhemoglobinuria (PNH), multiple sclerosis (MS), and rheumatoid arthritis(RA) and other disorders described further herein characterized in thatFormula I as described herein is used in the manufacture;

(e) a pharmaceutical formulation comprising an effective host-treatingamount of the Formula I or a pharmaceutically acceptable salt or prodrugthereof together with a pharmaceutically acceptable carrier or diluent;

(f) Formula I as described herein in substantially pure form, includingsubstantially isolated from other chemical entities (e.g., at least 90or 95%);

(g) processes for the manufacture of the compounds of Formula I andsalts, compositions, dosage forms thereof; and

(h) processes for the preparation of therapeutic products that containan effective amount of Formula I, as described herein.

DETAILED DESCRIPTION I. Terminology

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein includeenantiomers, mixtures of enantiomers, diastereomers, tautomers,racemates and other isomers, such as rotamers, as if each isspecifically described. “Formula I” includes all subgeneric groups ofFormula I, such as Formula IA and Formula IB and also includespharmaceutically acceptable salts of a compound of Formula I, unlessclearly contraindicated by the context in which this phrase is used.“Formula I” also includes all subgeneric groups of Formula I, such asFormulas IC-ID, and Formulas II-XXX, and also includes pharmaceuticallyacceptable salts of all subgeneric groups of Formula I, such as FormulasIA-ID, and Formulas II-XXX, unless contraindicated by the context inwhich this phrase is used.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed. Unless definedotherwise, technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The present invention includes compounds of Formula I and the use ofcompounds with at least one desired isotopic substitution of an atom, atan amount above the natural abundance of the isotope, i.e., enriched.Isotopes are atoms having the same atomic number but different massnumbers, i.e., the same number of protons but a different number ofneutrons.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I respectively. The invention includesisotopically modified compounds of Formula I. In one embodiment,isotopically labelled compounds can be used in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically labeled compounds ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the schemes or in the examplesand preparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen,for example, deuterium (²H) and tritium (³H) may be used anywhere indescribed structures that achieves the desired result. Alternatively orin addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used. In oneembodiment, the isotopic substitution is deuterium for hydrogen at oneor more locations on the molecule to improve the performance of thedrug, for example, the pharmacodynamics, pharmacokinetics,biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. Forexample, the deuterium can be bound to carbon in a location of bondbreakage during metabolism (an α-deuterium kinetic isotope effect) ornext to or near the site of bond breakage (a β-deuterium kinetic isotopeeffect).

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched in an isotope at any locationof interest. In one embodiments deuterium is 90, 95 or 99% enriched at adesired location. Unless otherwise stated, the enrichment at any pointis above natural abundance and enough to alter a detectable property ofthe drug in a human.

In one embodiment, the substitution of a hydrogen atom for a deuteriumatom occurs within an R group substituent on the L-B moiety region. Inone embodiment, the substitution of a hydrogen atom for a deuterium atomoccurs within an R group selected from any of R¹⁸, R^(18′), R³³, R³⁴,R³⁵, and/or R³⁶. In one embodiment, the substitution of a hydrogen atomfor a deuterium atom occurs within an R group substituent within theA-carbonyl moiety region. In one embodiment, the substitution of ahydrogen atom for a deuterium atom occurs at R^(4′) R⁵, R⁶, R^(6′), R⁷,R⁸, R^(8′), R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁹, R²¹, R²², R²³, R³⁰,and/or R^(30a). In other embodiments, certain substituents on theproline ring are selectively deuterated. For example, in one embodiment,the substitution of a hydrogen atom for a deuterium atom occurs at R,R′, R¹, R^(1′), R², R^(2′), R³, and/or R^(3′). In one embodiment, forexample, when any of the R substituents of the proline ring are methylor methoxy, the alkyl residue is optionally deuterated, e.g., CD₃ orOCD₃. In certain other embodiments, when two substituents of the prolinering are combined to form a cyclopropyl ring, the unsubstitutedmethylene carbon is deuterated.

The substitution of a hydrogen atom for a deuterium atom occurs withinan R group when at least one of the variables within the R group ishydrogen (e.g., ²H or D) or alkyl (e.g., CD₃). For example, when any ofR groups are, or contain for example through substitution, methyl orethyl, the alkyl residue is typically deuterated, e.g., CD₃, CH₂CD₃ orCD₂CD₃.

The compound of the present invention may form a solvate with solvents(including water). Therefore, in one embodiment, the invention includesa solvated form of the active compound. The term “solvate” refers to amolecular complex of a compound of the present invention (includingsalts thereof) with one or more solvent molecules. Examples of solventsare water, ethanol, dimethyl sulfoxide, acetone and other common organicsolvents. The term “hydrate” refers to a molecular complex comprising acompound of the invention and water. Pharmaceutically acceptablesolvates in accordance with the invention include those wherein thesolvent of crystallization may be isotopically substituted, e.g. D₂O,d₆-acetone, d₆-DMSO. A solvate can be in a liquid or solid form.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —(C═O)NH₂is attached through carbon of the keto (C═O) group.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a moietyselected from the indicated group, provided that the designated atom'snormal valence is not exceeded. For example, when the substituent is oxo(i.e., ═O) then two hydrogens on the atom are replaced. When an oxogroup replaces two hydrogens in an aromatic moiety, the correspondingpartially unsaturated ring replaces the aromatic ring. For example apyridyl group substituted by oxo is a pyridone. Combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds or useful synthetic intermediates.

A stable compound or stable structure refers to a compound leading to acompound that can be isolated and can be formulated into a dosage formwith a shelf life of at least one month.

Any suitable group may be present on a “substituted” or “optionallysubstituted” position that forms a stable molecule and advances thedesired purpose of the invention and includes, but is not limited to,e.g., halogen (which can independently be F, Cl, Br or I); cyano;hydroxyl; nitro; azido; alkanoyl (such as a C₂-C₆ alkanoyl group);carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy suchas phenoxy; alkylthio including those having one or more thioetherlinkages; alkylsulfinyl; alkylsulfonyl groups including those having oneor more sulfonyl linkages; aminoalkyl groups including groups having oneor more N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like,each ring either substituted or unsubstituted aromatic); arylalkylhaving for example, 1 to 3 separate or fused rings and from 6 to about14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkylgroup; arylalkoxy, for example, having 1 to 3 separate or fused ringswith benzyloxy being an exemplary arylalkoxy group; or a saturated,unsaturated, or aromatic heterocyclic group having 1 to 3 separate orfused rings with one or more N, O or S atoms, e.g. coumarinyl,quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl,pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl,isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl,piperazinyl, and pyrrolidinyl. Such heterocyclic groups may be furthersubstituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. Incertain embodiments “optionally substituted” includes one or moresubstituents independently chosen from halogen, hydroxyl, amino, cyano,—CHO, —COOH, —CONH₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,—C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆alkylester, (mono- anddi-C₁-C₆alkylamino)C₀-C₂alkyl, C₁-C₂haloalkyl, hydoxyC₁-C₆alkyl, ester,carbamate, urea, sulfonamide, —C₁-C₆alkyl(heterocyclo),C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(C₃-C₇cycloalkyl),O—C₁-C₆alkyl(C₃-C₇cycloalkyl), B(OH)₂, phosphate, phosphonate andC₁-C₂haloalkoxy.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbongroup. In one embodiment, the alkyl contains from 1 to about 12 carbonatoms, more generally from 1 to about 6 carbon atoms or from 1 to about4 carbon atoms. In one embodiment, the alkyl contains from 1 to about 8carbon atoms. In certain embodiments, the alkyl is C₁-C₂, C₁-C₃, orC₁-C₆. The specified ranges as used herein indicate an alkyl grouphaving each member of the range described as an independent species. Forexample, the term C₁-C₆ alkyl as used herein indicates a straight orbranched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and isintended to mean that each of these is described as an independentspecies. For example, the term C₁-C₄alkyl as used herein indicates astraight or branched alkyl group having from 1, 2, 3, or 4 carbon atomsand is intended to mean that each of these is described as anindependent species. When C₀-C_(n) alkyl is used herein in conjunctionwith another group, for example, (C₃-C₇cycloalkyl)C₀-C₄ alkyl, or—C₀-C₄alkyl(C₃-C₇cycloalkyl), the indicated group, in this casecycloalkyl, is either directly bound by a single covalent bond(C₀alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4carbon atoms. Alkyls can also be attached via other groups such asheteroatoms as in —O—C₀-C₄alkyl(C₃-C₇cycloalkyl). Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl,neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutaneand 2,3-dimethylbutane. In one embodiment, the alkyl group is optionallysubstituted as described above.

“Alkenyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon double bonds that may occur at a stablepoint along the chain. Nonlimiting examples are C₂-C₈alkenyl,C₂-C₆alkenyl and C₂-C₄alkenyl. The specified ranges as used hereinindicate an alkenyl group having each member of the range described asan independent species, as described above for the alkyl moiety.Examples of alkenyl include, but are not limited to, ethenyl andpropenyl. In one embodiment, the alkenyl group is optionally substitutedas described above.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon triple bonds that may occur at anystable point along the chain, for example, C₂-C₈alkynyl or C₂-C₆alkynyl.The specified ranges as used herein indicate an alkynyl group havingeach member of the range described as an independent species, asdescribed above for the alkyl moiety. Examples of alkynyl include, butare not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl and 5-hexynyl. In one embodiment, the alkynyl groupis optionally substituted as described above.

“Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example,can be a 1 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicatednumber of carbon atoms, for example C₁-C₄alkylene, C₁-C₃alkylene, orC₁-C₂alkylene.

“Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbondouble bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkenylene.

“Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbontriple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkynylene.

“Alkoxy” is an alkyl group as defined above covalently bound through anoxygen bridge (—O—). Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy,n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy,2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly an “alkylthio” or a“thioalkyl” group is an alkyl group as defined above with the indicatednumber of carbon atoms covalently bound through a sulfur bridge (—S—).In one embodiment, the alkoxy group is optionally substituted asdescribed above.

“Alkenyloxy” is an alkenyl group as defined covalently bound to thegroup it substitutes by an oxygen bridge (—O—).

“Alkanoyl” is an alkyl group as defined above covalently bound through acarbonyl (C═O) bridge. The carbonyl carbon is included in the number ofcarbons, that is C₂alkanoyl is a CH₃(C═O)— group. In one embodiment, thealkanoyl group is optionally substituted as described above.

“Alkylester” is an alkyl group as defined herein covalently boundthrough an ester linkage. The ester linkage may be in eitherorientation, e.g., a group of the formula —O(C═O)alkyl or a group of theformula —(C═O)Oalkyl.

“Amide” or “carboxamide” is —C(O)NR^(a)R^(b) wherein R^(a) and R^(b) areeach independently selected from hydrogen, alkyl, for example,C₁-C₆alkyl, alkenyl, for example, C₂-C₆alkenyl, alkynyl, for example,C₂-C₆alkynyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkyl(C₃-C₇heterocycloalkyl), —C₀-C₄alkyl(aryl), and—C₀-C₄alkyl(heteroaryl); or together with the nitrogen to which they arebonded, R^(a) and R^(b) can form a C₃-C₇heterocyclic ring. In oneembodiment, the R^(a) and R^(b) groups are each independently optionallysubstituted as described above.

“Carbocyclic group”, “carbocyclic ring”, or “cycloalkyl” is a saturatedor partially unsaturated (i.e., not aromatic) group containing allcarbon ring atoms. A carbocyclic group typically contains 1 ring of 3 to7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms.Cycloalkyl substituents may be pendant from a substituted nitrogen orcarbon atom, or a substituted carbon atom that may have two substituentscan have a cycloalkyl group, which is attached as a spiro group.Examples of carbocyclic rings include cyclohexenyl, cyclohexyl,cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropylrings. In one embodiment, the carbocyclic ring is optionally substitutedas described above. In one embodiment, the cycloalkyl is a partiallyunsaturated (i.e., not aromatic) group containing all carbon ring atoms.In another embodiment, the cycloalkyl is a saturated group containingall carbon ring atoms.

“Carbocyclic-oxy group” is a monocyclic carbocyclic ring or a mono- orbi-cyclic carbocyclic group as defined above attached to the group itsubstitutes via an oxygen, —O—, linker.

“Haloalkyl” indicates both branched and straight-chain alkyl groupssubstituted with 1 or more halogen atoms, up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl include, but are notlimited to, trifluoromethyl, monofluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined herein attachedthrough an oxygen bridge (oxygen of an alcohol radical).

“Hydroxyalkyl” is an alkyl group as previously described, substitutedwith at least one hydroxyl substituent.

“Aminoalkyl” is an alkyl group as previously described, substituted withat least one amino substituent.

“Halo” or “halogen” indicates independently any of fluoro, chloro,bromo, and iodo.

“Aryl” indicates aromatic groups containing only carbon in the aromaticring or rings. In one embodiment, the aryl groups contain 1 to 3separate or fused rings and is 6 to about 14 or 18 ring atoms, withoutheteroatoms as ring members. When indicated, such aryl groups may befurther substituted with carbon or non-carbon atoms or groups. Suchsubstitution may include fusion to a 5 to 7-membered saturated cyclicgroup that optionally contains 1 or 2 heteroatoms independently chosenfrom N, O, and S, to form, for example, a 3,4-methylenedioxyphenylgroup. Aryl groups include, for example, phenyl and naphthyl, including1-naphthyl and 2-naphthyl. In one embodiment, aryl groups are pendant.An example of a pendant ring is a phenyl group substituted with a phenylgroup. In one embodiment, the aryl group is optionally substituted asdescribed above.

The term “heterocycle,” or “heterocyclic ring” as used herein refers toa saturated or a partially unsaturated (i.e., having one or more doubleand/or triple bonds within the ring without aromaticity) carbocyclicradical of 3 to about 12, and more typically 3, 5, 6, 7 to 10 ring atomsin which at least one ring atom is a heteroatom selected from nitrogen,oxygen, phosphorus and sulfur, the remaining ring atoms being C, whereone or more ring atoms is optionally substituted independently with oneor more substituents described above. A heterocycle may be a monocyclehaving 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatomsselected from N, O, P, and S) or a bicycle having 6 to 10 ring members(4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, andS), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system. In oneembodiment, the only heteroatom is nitrogen. In one embodiment, the onlyheteroatom is oxygen. In one embodiment, the only heteroatom is sulfur.Heterocycles are described in Paquette, Leo A.; “Principles of ModernHeterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularlyChapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds,A series of Monographs” (John Wiley & Sons, New York, 1950 to present),in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc.(1960) 82:5566. Examples of heterocyclic rings include, but are notlimited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl,homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl,oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, dihydroisoquinolinyl,tetrahydroisoquinolinyl, pyrazolidinylimidazolinyl, imidazolidinyl,2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane,8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane,2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl,quinolizinyl, N-pyridyl ureas, and pyrrolopyrimidine. Spiro moieties arealso included within the scope of this definition. Examples of aheterocyclic group wherein 1 or 2 ring carbon atoms are substituted withoxo (═O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. Theheterocycle groups herein are optionally substituted independently withone or more substituents described herein.

“Heterocyclicoxy group” is a monocyclic heterocyclic ring or a bicyclicheterocyclic group as described previously linked to the group itsubstitutes via an oxygen, —O—, linker.

“Heteroaryl” indicates a stable monocyclic aromatic ring which containsfrom 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen fromN, O, and S, with remaining ring atoms being carbon, or a stablebicyclic or tricyclic system containing at least one 5- to 7-memberedaromatic ring which contains from 1 to 3, or in some embodiments from 1to 2, heteroatoms chosen from N, O, and S, with remaining ring atomsbeing carbon. In one embodiment, the only heteroatom is nitrogen. In oneembodiment, the only heteroatom is oxygen. In one embodiment, the onlyheteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5to 7 ring atoms. In some embodiments bicyclic heteroaryl groups are 9-to 10-membered heteroaryl groups, that is, groups containing 9 or 10ring atoms in which one 5- to 7-member aromatic ring is fused to asecond aromatic or non-aromatic ring. When the total number of S and Oatoms in the heteroaryl group exceeds 1, these heteroatoms are notadjacent to one another. In one embodiment, the total number of S and Oatoms in the heteroaryl group is not more than 2. In another embodiment,the total number of S and O atoms in the aromatic heterocycle is notmore than 1. Examples of heteroaryl groups include, but are not limitedto, pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl,imidazopyridinyl, pyrimidinyl (including, for example,4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, tetrahydrofuranyl, and furopyridinyl. Heteroaryl groupsare optionally substituted independently with one or more substituentsdescribed herein. “Heteroaryloxy” is a heteroaryl group as describedbound to the group it substituted via an oxygen, —O—, linker.

“Heterocycloalkyl” is a saturated ring group. It may have, for example,1, 2, 3, or 4 heteroatoms independently chosen from N, S, and O, withremaining ring atoms being carbon. In a typical embodiment, nitrogen isthe heteroatom. Monocyclic heterocycloalkyl groups typically have from 3to about 8 ring atoms or from 4 to 6 ring atoms. Examples ofheterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl,and pyrrolinyl.

The term “mono- and/or di-alkylamino” indicates secondary or tertiaryalkylamino groups, wherein the alkyl groups are independently chosenalkyl groups, as defined herein. The point of attachment of thealkylamino group is on the nitrogen. Examples of mono- and di-alkylaminogroups include ethylamino, dimethylamino, and methyl-propyl-amino.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, implants, particles, spheres, creams,ointments, suppositories, inhalable forms, transdermal forms, buccal,sublingual, topical, gel, mucosal, and the like. A “dosage form” canalso include an implant, for example an optical implant.

“Pharmaceutical compositions” are compositions comprising at least oneactive agent, such as a compound or salt of Formula I, and at least oneother substance, such as a carrier. “Pharmaceutical combinations” arecombinations of at least two active agents which may be combined in asingle dosage form or provided together in separate dosage forms withinstructions that the active agents are to be used together to treat anydisorder described herein.

“Pharmaceutically acceptable salts” includes derivatives of thedisclosed compounds in which the parent compound is modified by makinginorganic and organic, non-toxic, acid or base addition salts thereof.The salts of the present compounds can be synthesized from a parentcompound that contains a basic or acidic moiety by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, non-aqueous media like ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are typical, where practicable.Salts of the present compounds further include solvates of the compoundsand of the compound salts.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Lists of additionalsuitable salts may be found, e.g., in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418(1985).

The term “carrier” applied to pharmaceutical compositions/combinationsof the invention refers to a diluent, excipient, or vehicle with whichan active compound is provided.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition/combination that isgenerally safe, non-toxic and neither biologically nor otherwiseinappropriate for administration to a host, and includes, in oneembodiment, an excipient that is acceptable for veterinary use as wellas human pharmaceutical use. A “pharmaceutically acceptable excipient”as used in the present application includes both one and more than onesuch excipient.

A “patient” or “host” or “subject” is a human or non-human animal inneed of modulation of the complement factor D pathway. Typically thehost is a human. A “patient” or “host” or “subject” also refers to forexample, mammals, primates (e.g., humans), cows, sheep, goats, horses,dogs, cats, rabbits, rats, mice, fish, birds and the like.

A “prodrug” as used herein, means a compound which when administered toa host in vivo is converted into a parent drug. As used herein, the term“parent drug” means any of the presently described chemical compoundsthat are useful to treat any of the disorders described herein, or tocontrol or improve the underlying cause or symptoms associated with anyphysiological or pathological disorder described herein in a host,typically a human. Prodrugs can be used to achieve any desired effect,including to enhance properties of the parent drug or to improve thepharmaceutic or pharmacokinetic properties of the parent. Prodrugstrategies exist which provide choices in modulating the conditions forin vivo generation of the parent drug, all of which are deemed includedherein. Nonlimiting examples of prodrug strategies include covalentattachment of removable groups, or removable portions of groups, forexample, but not limited to acylation, phosphorylation, phosphonylation,phosphoramidate derivatives, amidation, reduction, oxidation,esterification, alkylation, other carboxy derivatives, sulfoxy orsulfone derivatives, carbonylation or anhydride, among others.

“Providing a compound of Formula I with at least one additional activeagent” means the compound of Formula I and the additional activeagent(s) are provided simultaneously in a single dosage form, providedconcomitantly in separate dosage forms, or provided in separate dosageforms for administration separated by some amount of time that is withinthe time in which both the compound of Formula I and the at least oneadditional active agent are within the blood stream of a patient. Incertain embodiments the compound of Formula I and the additional activeagent need not be prescribed for a patient by the same medical careworker. In certain embodiments the additional active agent or agentsneed not require a prescription. Administration of the compound ofFormula I or the at least one additional active agent can occur via anyappropriate route, for example, oral tablets, oral capsules, oralliquids, inhalation, injection, suppositories or topical contact.

A “therapeutically effective amount” of a pharmaceuticalcomposition/combination of this invention means an amount effective,when administered to a patient, to provide a therapeutic benefit such asan amelioration of symptoms, e.g., an amount effective to decrease thesymptoms of a macular degeneration. In one embodiment, a therapeuticallyeffective amount is an amount sufficient to prevent a significantincrease or will significantly reduce the detectable level of complementfactor D in the patient's blood, serum, or tissues.

II. Detailed Description of the Active Compounds

According to the present invention, a compound of Formula I is provided:

as well as the pharmaceutically acceptable salts and compositionsthereof. Formula I can be considered to have a central core, an L-Bsubstituent, and a (C═O)A substituent. It has been surprisinglydiscovered that a compound of Formula I, or a pharmaceuticallyacceptable salt or composition thereof, wherein R¹² or R¹³ on the Agroup is an alkyne (R³²), is a superior inhibitor of complement factorD, and therefore can be used as an effective amount to treat a host inneed of complement factor D modulation.

Non-limiting examples of compounds falling within Formula I withvariations in the variables e.g., A, B, R¹-R^(3′), and L, areillustrated below. The disclosure includes all combinations of thesedefinitions so long as a stable compound results.

Formulas II-XXX

In one aspect, the disclosure includes compounds and salts of FormulaII, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII,XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIXand XXX which are within the scope of Formula I. The variables shown inFormula II-XXX carry the definitions set forth in the SUMMARY sectionfor Formula I or any of the definitions set forth in this disclosure.

In these embodiments, it should be understood that where R¹ or R³ isattached to a carbon, there can be two independent attachments as inR²/R^(2′) and these formulas should be considered to include all suchvariations.

Additionally, the disclosure includes compounds and salts of Formula Iand pharmaceutically acceptable compositions thereof, and any of itssubformulae (II-XXX) in which at least one of the following conditionsis met in the embodiments described below.

The R¹² and R¹³ Alkynyl Substituents

It has been surprisingly discovered that a compound of Formula I, apharmaceutically acceptable salt or composition thereof, wherein R¹² orR¹³ on the A group is an alkyne, is a superior inhibitor of complementfactor D. In one embodiment, the alkyne is directly linked to the Agroup. In another embodiment, the alkyne is indirectly linked to the Agroup through a linking moiety, wherein the linking moiety isC₁-C₄alkylene.

One of R¹² and R¹³ is chosen from R³¹ and the other of R¹² and R¹³ ischosen from R³². In another embodiment each of R¹² and R¹³ can beindependently selected from R³².

R³¹ is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino,—COOH, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₂-C₆alkenyloxy, —C(O)OR⁹, C₁-C₆thioalkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and —C(NR⁹)NR⁹R¹⁰, each ofwhich R³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy is unsubstituted or substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, amino, —COOH, —CONH₂ C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,and each of which R³¹ is also optionally substituted with onesubstituent chosen from phenyl and 4- to 7-membered heterocyclecontaining 1, 2, or 3 heteroatoms independently chosen from N, O, and S;which phenyl or 4- to 7-membered heterocycle is unsubstituted orsubstituted with one or more substituents independently chosen fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl)(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, andC₁-C₂haloalkoxy;

R³² is —C₂-C₆alkynylR³⁰, and each R³² can be optionally substituted.Examples of R³² include, for example, but are not limited to,

In certain embodiments, R³² is selected from:

Non-Limiting R¹²/R¹³ Embodiments

In one embodiment, R¹² is R³².

In one embodiment, R¹³ is R³².

In one embodiment, R¹² is R³², which is C₂-C₄alkynylR³⁰.

In one embodiment, R¹³ is R³², which is C₂-C₄alkynylR³⁰.

In one embodiment, the disclosure provides compounds of Formula I,wherein;

one of R¹² and R¹³ is H and the other of R¹² and R¹³ is R³², where

R³² is C₂-C₆alkynylR³⁰ (which can be, for example, C₂-C₃alkynylR³⁰,C₂-C₄alkynylR³⁰, C₂-C₅alkynylR³⁰, or C₂-C₆alkynylR³⁰), wherein R³⁰ isindependently chosen at each occurrence from hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(phenyl)C₀-C₄alkyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkyl having1, 2, or 3 heteroatoms independently chosen from N, O, and S; (5- or6-membered unsaturated or aromatic heterocycle)C₀-C₄alkyl having 1, 2,or 3 heteroatoms independently chosen from N, O, and S; COOH, Si(CH₃)₃,COOR^(30a), C₂-C₆alkanoyl, —C(O)(CH₂)₁₋₄S(O)R²¹, —P(O)(OR²¹)(OR²²),—P(O)R²¹R²², —NR²¹SO₂R²², —NR⁹SO₂NR¹⁰R²², —SO₂NR⁹COR²²,—SO₂NR⁹CONR²¹R²², —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR¹⁰C(O)R²²,—(CH₂)₁₋₄C(O)NR²¹R²², —C(O)R²⁴R²⁵, —C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰,—NR⁹C(O)NR²⁴R²⁵, —(CH₂)₁₋₄OC(O)R²¹, each of which R³⁰ can be optionallysubstituted;

wherein R⁹, R¹⁰, R²¹, R²², R²⁴, R²⁵, and R^(30a) are as defined in thesummary section above.

In another embodiment, the disclosure provides compounds of Formula I,wherein;

R¹, R^(1′), R², and R^(3′) are all hydrogen;

R² is fluoro and R³ is hydrogen, —C₀-C₄alkyl(C₃-C₇cycloalkyl), or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R⁵ is hydrogen, halogen, or C₁-C₂alkyl;

R¹¹, R¹³, R¹⁴, and R¹⁵ if present, are independently chosen at eachoccurrence from hydrogen, halogen, hydroxyl, amino, C₁-C₄alkyl,C₁-C₄alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₂alkylamino), trifluoromethyl,and trifluoromethoxy;

X¹² is CR¹²; and

R¹² is C₂-C₆alkynylR³⁰.

In one embodiment, the disclosure provides compounds of Formula I,wherein;

m is 0 or 1;

R² is halogen, R^(2′) is hydrogen or halogen, and R³ is hydrogen,halogen, —C₀-C₄alkyl(C₃-C₇cycloalkyl), or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R⁶ is —C(O)C₁-C₄alkyl, —C(O)NH₂, —C(O)CF₃, —C(O)(C₃-C₇cycloalkyl), or-ethyl(cyanoimino);

one of R¹² and R¹³ is selected from hydrogen, halogen, C₁-C₄alkyl,C₁-C₄alkoxy, trifluoromethyl, and trifluoromethoxy; the other of R¹² andR¹³ is R³², where

R³² is C₂-C₆alkynylR³⁰, wherein R³⁰ is independently chosen at eachoccurrence from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S; (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S; COOH, Si(CH₃)₃, COOR^(30a), C₂-C₆alkanoyl,—B(OH)₂, —C(O)(CH₂)₁₋₄S(O)R²¹, —P(O)(OR²¹)(OR²²), —P(O)(OR²¹)R²²,—P(O)R²¹R²², —NR⁹P(O)(NHR²¹)(NHR²²), —NR⁹P(O)(OR²¹)(NHR²²),—NR⁹P(O)(OR²¹)(OR²²), —C(S)R²¹, —NR²¹SO₂R²², —NR⁹S(O)NR¹⁰R²²,—NR⁹SO₂NR¹⁰R²², —SO₂NR⁹COR²², —SO₂NR⁹CONR²¹R²², —NR²¹SO₂R²²,—C(O)NR²¹SO₂R²², —C(NH₂)NR⁹R²², —C(NH₂)NR⁹S(O)₂R²², —NR⁹C(O)OR¹,—NR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², —C(O)R²⁴R²⁵, —NR⁹C(O)R²¹, —C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR²⁴R²⁵, —(CH₂)₁₋₄OC(O)R²¹, each of which R³⁰can be optionally substituted;

wherein R⁹, R¹⁰, R²¹, R²², R²⁴, R²⁵, and R^(30a) are as defined in thesummary section above.

In one embodiment, the disclosure provides compounds of Formula I,wherein;

one of R¹² and R¹³ is hydrogen, hydroxyl, halogen, methyl, or methoxy;and the other of R¹² and R¹³ is R³², where

R³² is C₂-C₆alkynylR³⁰, wherein R³⁰ is independently chosen at eachoccurrence from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S; (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S; COOH, Si(CH₃)₃, COOR^(30a), C₂-C₆alkanoyl,—B(OH)₂, —C(O)(CH₂)₁₋₄S(O)R²¹, —P(O)(OR²¹)(OR²²), —P(O)(OR²¹)R²²,—P(O)R²¹R²², —NR⁹P(O)(NHR²¹)(NR²²), —NR⁹P(O)(OR²¹)(NHR²²),—NR⁹P(O)(OR²¹)(OR²²), —C(S)R²¹, —NR²¹SO₂R²², —NR⁹S(O)NR¹⁰R²²,—NR⁹SO₂NR¹⁰R²², —SO₂NR⁹COR²², —SO₂NR⁹CONR²¹R²², —NR²¹SO₂R²²,—C(O)NR²¹SO₂R²², —C(NH₂)NR⁹R²², —C(NH₂)NR⁹S(O)₂R²², —NR⁹C(O)OR¹,—NR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², —C(O)R²⁴R²⁵, —NR⁹C(O)R²¹, —C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR²⁴R²⁵, —(CH₂)₁₋₄OC(O)R²¹, each of which R³⁰can be optionally substituted;

wherein R⁹, R¹⁰, R²¹, R²², R²⁴, R²⁵, and R^(30a) are as defined in thesummary section above.

In one embodiment, R³² may be unsubstituted or substituted with one ormore substituents independently chosen from halogen, hydroxyl, nitro,cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂, —P(O)(OH)₂,C₁-C₆alkyl, C₁-C₆alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino),C₁-C₆alkylester, C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.

Central Core Moiety

The central core moiety in Formula I is illustrated below:

wherein:

Q¹ is N(R¹) or C(R¹R^(1′));

Q² is C(R²R^(2′)), C(R²R^(2′))—C(R²R^(2′)), S, O, N(R²) or C(R²R^(2′))O;

Q³ is N(R³), S, or C(R³R^(3′));

X¹ and X² are independently N or CH, or X¹ and X² together are C═C; and

wherein Q¹, Q², Q³, X¹, and X² are selected such that a stable compoundresults.

Non-limiting examples of the

ring are illustrated below (any of which can be otherwise substitutedwith R¹, R^(1′), R², R^(2′), R³, and R^(3′)) as described in more detailbelow.

wherein q is, 2 or 3 and r is, 2 or 3.

R and R′ are independently chosen from H, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, aralkyl,heteroaryl, heteroarylalkyl wherein each group can be optionallysubstituted or any other substituent group herein that provides thedesired properties. In some embodiments, the ring includes one or morechiral carbon atoms. The invention includes embodiments in which thechiral carbon can be provided as an enantiomer, or mixtures ofenantiomers, including a racemic mixture. Where the ring includes morethan one stereocenter, all of the enantiomers and diastereomers areincluded in the invention as individual species.

Z is F, Cl, NH₂, CH₃, CH₂D, CHD₂, or CD₃.

R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently chosen at eachoccurrence, as appropriate, and only where a stable compound results,from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkynyl, C₂-C₆alkanoyl,C₁-C₆thioalkyl, hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)OR⁹, —OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰,—NR⁹C(O)OR¹⁰, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, where R⁹ and R¹⁰ areindependently chosen at each occurrence from hydrogen, C₁-C₆alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), and—O—C₀-C₄alkyl(C₃-C₇cycloalkyl).

Non-Limiting Central Core Embodiments

In alternative embodiments, R¹ and R^(1′) or R³ and R^(3′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring or a 3- to6-membered heterocyclic spiro ring containing 1 or 2 heteroatomsindependently chosen from N, O, or S; R² and R^(2′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring; or R² andR^(2′) may be taken together to form a 3- to 6-membered heterocyclicspiro ring each of which ring may be unsubstituted or substituted with 1or more substituents independently chosen from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In alternative embodiments, R¹ and R² may be taken together to form a3-membered carbocyclic ring; R¹ and R² may be taken together to form a4- to 6-membered carbocyclic or aryl ring or a 4- to 6-memberedheterocyclic or heteroaryl ring containing 1 or 2 heteroatomsindependently chosen from N, O, and S; or R² and R³, if bound toadjacent carbon atoms, may be taken together to form a 3- to 6-memberedcarbocyclic or aryl ring or a 3- to 6-membered heterocyclic orheteroaryl ring each of which ring may be unsubstituted or substitutedwith one or more substituents independently chosen from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In one embodiment, the central core moiety is proline.

In one embodiment, the central core moiety is 4-fluoroproline.

In one embodiment, R¹, R^(1′), R^(2′), R³, and R^(3′), if present, areall hydrogen; and R² is fluoro.

In one embodiment, R¹, R^(1′), R^(2′), and R^(3′), if present, are allhydrogen; and R² is fluoro and R³ is —C₀-C₄alkyl(C₃-C₇cycloalkyl) or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl).

In one embodiment, R¹ and R² are taken together to form a 3- to6-membered cycloalkyl group, and R^(1′), R^(2′), R³, and R^(3′), wherepresent, are all hydrogen.

In one embodiment, R¹, R^(1′), R³, and R^(3′), if present, are allhydrogen, and R² and R^(2′) are taken together to form a 5- or6-membered heterocycloalkyl group having 1 or 2 oxygen atoms.

In one embodiment, R¹ is hydrogen and R² is fluoro.

In one embodiment, R¹ and R² are joined to form a 3 membered ring.

The disclosure includes compounds of Formula I in which the centralpyrrolidine is vinyl substituted, for example:

In one embodiment, the compound of Formula I has the structure:

In one embodiment, the central pyrrolidine is modified by addition of asecond heteroatom to a pyrrolidine ring, such as N, O, S, or Si, forexample:

Another modification within the scope of the disclosure is joining asubstituent on the central pyrrolidine ring to R⁷ or R⁸ to form a 5- to6-membered heterocyclic ring, for example:

Example of compounds having the modifications disclosed above include:

Central Core L-B Substituents

The central core L-B substituents in Formula I are illustrated below:

L is a bond or is chosen from the formulas:

where R¹⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl) andR¹⁸ and R^(18′) are independently chosen from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.

B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicycliccarbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclicgroup having 1, 2, 3, or 4 heteroatoms independently selected from N, O,and S and from 4 to 7 ring atoms per ring; C₂-C₆alkenyl; C₂-C₆alkynyl;—(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); or—(C₀-C₄alkyl)(biphenyl).

Each of which B is unsubstituted or substituted with one or moresubstituents independently chosen from R³³ and R³⁴, and 0 or 1substituents chosen from R³⁵ and R³⁶:

R³³ is independently chosen from halogen, hydroxyl, —COOH, cyano,C₁-C₆alkyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R³⁴ is independently chosen from nitro, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR^(21)(O)R²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(o)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹R²²,-JNR⁹SO₂NR¹R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)NR²², -JC(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JC(O)R²⁴R²⁵,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄OC(O)R²¹,and -JC(O)OR²³; each of which R³⁴ may be unsubstituted or substitutedwith one or more substituents independently chosen from halogen,hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂,—P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy,—C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy;

R³⁵ is independently chosen from naphthyl, naphthyloxy, indanyl, (4- to7-membered heterocycloalkyl)C₀-C₄alkyl containing 1 or 2 heteroatomschosen from N, O, and S, and bicyclic heterocycle containing 1, 2, or 3heteroatoms independently chosen from N, O, and S, and containing 4- to7-ring atoms in each ring; each of which R³⁵ is unsubstituted orsubstituted with one or more substituents independently chosen fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy; and

R³⁶ is independently chosen from tetrazolyl, (phenyl)C₀-C₂alkyl,(phenyl)C₁-C₂alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing1, 2, or 3 heteroatoms independently chosen from N, O, B, and S, each ofwhich R³⁶ is unsubstituted or substituted with one or more substituentsindependently chosen from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, —OSi(CH₃)₂C(CH₃)₃,—Si(CH₃)₂C(CH₃)₃, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

J is independently chosen at each occurrence from a covalent bond,C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, and C₂-C₄alkynylene.

In one embodiment, -L-B— is

whereR²⁶ and R²⁷ are independently chosen from hydrogen, halogen, hydroxyl,nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₁-C₆thioalkyl, —C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino),—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkoxy(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and C₁-C₂haloalkylthio.

Non-Limiting L-B Embodiments

In another embodiment, -L-B— is

wherein

R¹⁸ and R^(18′) are independently chosen from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0 or 1; and

R²⁶, R²⁷, and R²⁸ are independently chosen from hydrogen, halogen,hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,C₁-C₆alkoxy, C₁-C₆thioalkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl-, (heteroaryl)C₀-C₄alkyl-,and —C₀-C₄alkoxy(C₃-C₇cycloalkyl); each of which R²⁶, R²⁷, and R²⁸ otherthan hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted orsubstituted with one or more substituents independently chosen fromhalogen, hydroxyl, amino, C₁-C₂alkoxy, C₁-C₂haloalkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl-, and C₁-C₂haloalkoxy; and

R²⁹ is hydrogen, C₁-C₂alkyl, C₁C₂haloalkyl or —Si(CH₃)₂C(CH₃)₃.

In one embodiment, m is 0.

In one embodiment, the disclosure further includes compounds and saltsof Formula I in which B is 2-fluoro-3-chlorophenyl. In anotherembodiment, another carbocyclic, aryl, heterocyclic, or heteroaryl groupsuch as 2-bromo-pyridin-6-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl,2,2-dichlorocyclopropylmethyl, or 2-fluoro-3-trimethylsilylphenyl isused.

In another embodiment, B is phenyl, pyridyl, or indanyl each of which isunsubstituted or substituted with one or more substituents independentlychosen from hydrogen, halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—C₀-C₄alkoxy(C₃-C₇cycloalkyl), (phenyl)C₀-C₂alkyl, (pyridyl)C₀-C₂alkyl;each of which substituents other than hydrogen, halogen, hydroxyl,nitro, cyano, is unsubstituted or substituted with one or moresubstituents independently chosen from halogen, hydroxyl, amino,C₁-C₂alkyl, C₁-C₂alkoxy, —OSi(CH₃)₂C(CH₃)₃, —Si(CH₃)₂C(CH₃)₃,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In another embodiment, B is phenyl or pyridyl substituted with 1, 2, or3 substituents chosen from chloro, bromo, hydroxyl, —SCF₃, C₁-C₂alkyl,C₁-C₂alkoxy, trifluoromethyl, phenyl and trifluoromethoxy each of whichsubstituents other than chloro, bromo, hydroxyl, —SCF₃, can beoptionally substituted.

In certain embodiments, B is a 2-fluoro-3-chlorophenyl or a2-fluoro-3-trifluoromethoxyphenyl group.

In one embodiment, B is pyridyl, optionally substituted with halogen,C₁-C₂alkoxy, and trifluoromethyl.

In one embodiment, B is phenyl, substituted with 1, 2, or 3 substituentsindependently selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,trifluoromethyl, and optionally substituted phenyl.

In one embodiment, R²³ is independently chosen at each occurrence from(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S.

In one embodiment, B is selected from

where R²⁷ is hydrogen, methyl, or trifluoromethyl; R²⁸ is hydrogen orhalogen; and R²⁹ is hydrogen, methyl, trifluoromethyl, or—Si(CH₃)₂C(CH₃)₃.

Central Core (C═O)A Substituent

The central core (C═O)A substituent in Formula I is illustrated below:

A is a group chosen from:

R⁴ is chosen from —CHO, —CONH₂, C₂-C₆alkanoyl, hydrogen, —SO₂NH₂,—C(CH₂)₂F, —CH(CF₃)NH₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₂alkyl(C₃-C₇cycloalkyl),

each of which R⁴ other than hydrogen, —CHO, and —CONH₂, is unsubstitutedor substituted with one or more of amino, imino, halogen, hydroxyl,cyano, cyanoimino, C₁-C₂alkyl, C₁-C₂alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R⁵ and R⁶ are independently chosen from —CHO, —C(O)NH₂, —C(O)NH(CH₃),C₂-C₆alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH,—SO₂NH₂, vinyl, C₁-C₆alkyl (including methyl), C₂-C₆alkenyl,C₁-C₆alkoxy, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl), —P(O)(OR⁹)₂, —OC(O)R⁹, —C(O)OR⁹,—C(O)N(CH₂CH₂R⁹)(R¹⁰), —NR⁹C(O)R¹⁰, phenyl, or 5- to 6-memberedheteroaryl.

Each R⁵ and R⁶ other than hydrogen, hydroxyl, cyano, and —COOH isunsubstituted or optionally substituted. For example, R⁵ and R⁶, otherthan hydrogen, hydroxyl, cyano, —COOH, may be substituted with one ormore substituents independently chosen from halogen, hydroxyl, amino,imino, cyano, cyanoimino, C₁-C₂alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R^(6′) is hydrogen, halogen, hydroxyl, C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), or C₁-C₄alkoxy; or R⁶ and R^(6′) may betaken together to form an oxo, vinyl, or imino group.

R⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl).

R⁸ and R^(8′) are independently chosen from hydrogen, halogen, hydroxyl,C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) can be taken together with the carbonthat they are bonded to form a 3-membered carbocyclic ring.

R¹⁶ is absent or may include one or more substituents independentlychosen from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino),—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R¹⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,—SO₂C₁-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(C₃-C₇heterocycloalkyl),—C₀-C₄alkyl(aryl), C₀-C₄alkyl(heteroaryl), and wherein R¹⁹ other thanhydrogen is unsubstituted or substituted with 1 or more substituentsindependently chosen from halogen, hydroxyl, amino, —COOH, and—C(O)OC₁-C₄alkyl.

X¹¹ is N or CR¹¹.

X¹² is N or CR¹².

X¹³ is N or CR¹³.

X¹⁴ is N or CR¹⁴.

No more than 2 of X¹¹, X¹², X¹³, and X¹⁴ are N.

R¹¹, R¹⁴, and R¹⁵ are independently chosen at each occurrence fromhydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₂-C₆alkenyl(aryl),C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), C₂-C₆alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In one embodiment, R⁵ and R⁶ are independently chosen from —CHO,—C(O)NH₂, —C(O)NH(CH₃), C₂-C₆alkanoyl, and hydrogen.

In one embodiment, each R⁵ and R⁶ other than hydrogen, hydroxyl, cyano,and —COOH is unsubstituted or substituted with one or more substituentsindependently chosen from halogen, hydroxyl, amino, imino, cyano,cyanoimino, C₁-C₂alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In one embodiment, R⁸ and R^(8′) are independently hydrogen or methyl.

In one embodiment, R⁸ and R^(8′) are hydrogen.

In one embodiment, R⁷ is hydrogen or methyl.

In one embodiment, R⁷ is hydrogen.

Embodiments of Formulas IA, IB, IC, and ID

To further illustrate the invention, various embodiments of Formula IA,IB, IC and ID are provided. These are presented by way of example toshow some of the variations among presented compounds within theinvention and can be applied to any of the Formulas I-XXX.

In one aspect, this disclosure includes compounds and salts of FormulaIA:

whereR⁶, R¹³, and B may carry any of the definitions set forth herein forthis variable.

In another aspect, this disclosure includes compounds and salts ofFormula IB, IC, and ID.

In Formulas IA, IB, IC, and ID, the variables may include any of thedefinitions set forth herein that results in a stable compound. Incertain embodiments, the following conditions apply for Formula IB andIC.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is alkynylR³⁰,R³⁰ is heteroaryl, R¹³ is H, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is alkynylR³⁰, R³⁰ is heteroaryl, R¹³ is H, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is amide, R¹² is alkynylR³⁰, R³⁰is heteroaryl, R¹³ is H, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is alkynylR³⁰, R³⁰ is heteroaryl, R¹³ is H, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is H, R¹³ isalkynylR³⁰, R³⁰ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is H, R¹³ is alkynylR³⁰, R³⁰ is heteroaryl, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is amide, R¹² is H, R¹³ isalkynylR³⁰, R³⁰ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is H, R¹³ is alkynylR³⁰, R³⁰ is heteroaryl, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is alkynylR³⁰,R³⁰ is heteroaryl, R¹³ is H, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is alkynylR³⁰, R³⁰ is heteroaryl, R¹³ is H, and B isphenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is amide, R¹² is alkynylR³⁰, R³⁰is heteroaryl, R¹³ is H, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is alkynylR³⁰, R³⁰ is heteroaryl, R¹³ is H, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is H, R¹³ isalkynylR³⁰, R³⁰ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is H, R¹³ is alkynylR³⁰, R³⁰ is heteroaryl, and B isphenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is amide, R¹² is H, R¹³ isalkynylR³⁰, R³⁰ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is H, R¹³ is alkynylR³⁰, R³⁰ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is alkynylR³⁰,R³⁰ is heteroaryl, R¹³ is H, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is alkynylR³⁰, R³⁰ is heteroaryl, R¹³ is H, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is amide, R¹² is alkynylR³⁰, R³⁰is heteroaryl, R¹³ is H, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is alkynylR³⁰, R³⁰ is heteroaryl, R¹³ is H, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is H, R¹³ isalkynylR³⁰, R³⁰ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is H, R¹³ is alkynylR³⁰, R³⁰ is heteroaryl, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is amide, R¹² is H, R¹³ isalkynylR³⁰, R³⁰ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is H, R¹³ is alkynylR³⁰, R³⁰ is heteroaryl, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is alkynylR³⁰,R³⁰ is heteroaryl, R¹³ is H, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is alkynylR³⁰, R³⁰ is heteroaryl, R¹³ is H, and B isphenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is amide, R¹² is alkynylR³⁰, R³⁰is heteroaryl, R¹³ is H, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is alkynylR³⁰, R³⁰ is heteroaryl, R¹³ is H, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is H, R¹³ isalkynylR³⁰, R³⁰ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is H, R¹³ is alkynylR³⁰, R³⁰ is heteroaryl, and B isphenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is amide, R¹² is H, R¹³ isalkynylR³⁰, R³⁰ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is H, R¹³ is alkynylR³⁰, R³⁰ is heteroaryl, and B is phenyl.

Embodiments of Formula VII

To further illustrate the invention, various embodiments of Formula VII.In one aspect, the disclosure includes compounds and salts of FormulaVII:

wherein:

R¹, R², R^(2′), and R³ are independently chosen from hydrogen, halogen,C₁-C₄alkyl, C₁-C₄alkoxy, —C₀-C₂alkylNR⁹R¹⁰,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R⁸ and R^(8′) are independently chosen from hydrogen, halogen, andmethyl;

R⁵ is hydrogen, hydroxyl, cyano, —COOH, C₁-C₆alkyl, C₁-C₆alkoxy,C₂-C₆alkanoyl —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl, C₁-C₂haloalkyl, or C₁-C₂haloalkoxy;

R⁶ is —C(O)CH₃, —C(O)NH₂, —C(O)CF₃, —C(O)(cyclopropyl), or-ethyl(cyanoimino); and

R¹¹ and R¹⁴ are independently chosen from hydrogen, halogen, hydroxyl,amino, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,C₁-C₆alkoxy, C₁-C₆thioalkyl, —C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino),—C₀-C₄alkyl(C₃-C₇cycloalkyl), —OC₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

Prodrugs of Formula I are also within the scope of the disclosure.

III. Pharmaceutical Preparations

Compounds disclosed herein can be administered as the neat chemical, butcan also administered as a pharmaceutical composition, that includes aneffective amount for a host in need of treatment of the selectedcompound of Formula I, as described herein. Accordingly, the disclosureprovides pharmaceutical compositions comprising an effective amount ofcompound or pharmaceutically acceptable salt of Formula I, together withat least one pharmaceutically acceptable carrier. The pharmaceuticalcomposition may contain a compound or salt of Formula I as the onlyactive agent, or, in an alternative embodiment, Formula I and at leastone additional active agent. In certain embodiments the pharmaceuticalcomposition is in a dosage form that contains from about 0.1 mg to about2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about800 mg, or from about 200 mg to about 600 mg of a compound of Formula Iand optionally from about 0.1 mg to about 2000 mg, from about 10 mg toabout 1000 mg, from about 100 mg to about 800 mg, or from about 200 mgto about 600 mg of an additional active agent in a unit dosage form.Examples are dosage forms with at least 25, 50, 100, 200, 250, 300, 400,500, 600, 700, or 750 mg of active compound, or its salt. Thepharmaceutical composition may also include a molar ratio of a compoundof Formula I and an additional active agent. For example thepharmaceutical composition may contain a molar ratio of about 0.5:1,about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of ananother anti-inflammatory agent.

Compounds disclosed herein may be administered orally, topically,parenterally, by inhalation or spray, sublingually, via implant,including ocular implant, transdermally, via buccal administration,rectally, as an ophthalmic solution, injection, including ocularinjection, intraveneous, intra-aortal, intracranial, or by other means,in dosage unit formulations containing conventional pharmaceuticallyacceptable carriers. The pharmaceutical composition may be formulated asany pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, apill, a capsule, a tablet, a syrup, a transdermal patch, or anophthalmic solution. Some dosage forms, such as tablets and capsules,are subdivided into suitably sized unit doses containing appropriatequantities of the active components, e.g., an effective amount toachieve the desired purpose.

Carriers include excipients and diluents and must be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the patient being treated. The carrier can be inert orit can possess pharmaceutical benefits of its own. The amount of carrieremployed in conjunction with the compound is sufficient to provide apractical quantity of material for administration per unit dose of thecompound.

Classes of carriers include, but are not limited to binders, bufferingagents, coloring agents, diluents, disintegrants, emulsifiers,flavorants, glidents, lubricants, preservatives, stabilizers,surfactants, tableting agents, and wetting agents. Some carriers may belisted in more than one class, for example vegetable oil may be used asa lubricant in some formulations and a diluent in others. Exemplarypharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Optional active agents may be included in a pharmaceuticalcomposition, which do not substantially interfere with the activity ofthe compound of the present invention.

The pharmaceutical compositions/combinations can be formulated for oraladministration. These compositions can contain any amount of activecompound for Formula I that achieves the desired result, for examplebetween 0.1 and 99 weight % (wt. %) of a compound of Formula I andusually at least about 5 wt. % of a compound of Formula I. Someembodiments contain from about 25 wt. % to about 50 wt. % or from about5 wt. % to about 75 wt. % of the compound of Formula I.

The complement factor D inhibitors of the present invention can beadministered, for example, either systemically or locally. Systemicadministration includes, for example, oral, transdermal, subdermal,intraperitioneal, subcutaneous, transnasal, sublingual, or rectal. Localadministration for ocular administration includes: topical,intravitreal, periocular, transscleral, retrobulbar, juxtascleral,sub-tenon, or via an intraocular device. The inhibitors may be deliveredvia a sustained delivery device implanted intravitreally ortranssclerally, or by other known means of local ocular delivery.

IV. Methods of Treatment

The compounds and pharmaceutical compositions disclosed herein areuseful for treating or preventing a disorder that is mediated by thecomplement pathway, and in particular, a pathway that is modulated bycomplement factor D. In certain embodiments, the disorder is aninflammatory disorder, an immune disorder, an autoimmune disorder, orcomplement factor D related disorders in a host. In one embodiment, thedisorder is an ocular disorder. Complement mediated disorders that maybe treated or prevented by the compounds and compositions of thisdisclosure include, but are not limited to, inflammatory effects ofsepsis, systemic inflammatory response syndrome (SIRS),ischemia/reperfusion injury (I/R injury), psoriasis, myasthenia gravis,system lupus erythematosus (SLE), paroxysmal nocturnal hemoglobinuria(PNH), hereditary angioedema, multiple sclerosis, trauma, burn injury,capillary leak syndrome, obesity, diabetes, Alzheimer's dementia,stroke, schizophrenia, epilepsy, age-related macular degeneration,glaucoma, diabetic retinopathy, asthma, allergy, acute respiratorydistress syndrome (ARDS), atypical hemolytic uremic syndrome (aHUS),hemolytic uremic syndrome (HUS), cystic fibrosis, myocardial infarction,lupus nephritides, Crohn's disease, rheumatoid arthritis,atherosclerosis, transplant rejection, prevention of fetal loss,biomaterial reactions (e.g. in hemodialysis, inplants), C3glomerulonephritis, abdominal aortic aneurysm, neuromyelitis optica(NMO), vasculitis, neurological disorders, Guillain Barre Syndrome,traumatic brain injury, Parkinson's disease, disorders of inappropriateor undesirable complement activation, hemodialysis complications,hyperacute allograft rejection, xenograft rejection, interleukin-2induced toxicity during I L-2 therapy, inflammatory disorders,inflammation of autoimmune diseases, adult respiratory distresssyndrome, thermal injury including burns or frostbite, myocarditis,post-ischemic reperfusion conditions, balloon angioplasty, post-pumpsyndrome in cardiopulmonary bypass or renal bypass, hemodialysis, renalischemia, mesenteric artery reperfusion after aortic reconstruction,immune complex disorders and autoimmune diseases, SLE nephritis,proliferative nephritis, liver fibrosis, hemolytic anemia, tissueregeneration and neural regeneration. In addition, other knowncomplement related disease are lung disease and disorders such asdyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD),emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dustdiseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium,and asbestos), pulmonary fibrosis, organic dust diseases, chemicalinjury (due to irritant gases and chemicals, e.g., chlorine, phosgene,sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, andhydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze),bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases,Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis,immune complex-associated inflammation, uveitis (including Behcet'sdisease and other sub-types of uveitis), antiphospholipid syndrome,arthritis, autoimmune heart disease, inflammatory bowel disease,ischemia-reperfusion injuries, Barraquer-Simons Syndrome, hemodialysis,systemic lupus, lupus erythematosus, transplantation, diseases of thecentral nervous system and other neurodegenerative conditions,glomerulonephritis (including membrane proliferativeglomerulonephritis), blistering cutaneous diseases (including bullouspemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatricalpemphigoid, MPGN II, uveitis, adult macular degeneration, diabeticretinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis,multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediateuveitis, birdshot retino-chorioditis, sympathetic ophthalmia, oculardicatricial pemphigoid, ocular pemphigus, nonartertic ischemic opticneuropathy, postoperative inflammation, and retinal vein occlusion.

In some embodiments, complement mediated diseases include ophthalmicdiseases (including early or neovascular age-related maculardegeneration and geographic atrophy), autoimmune diseases (includingarthritis, rheumatoid arthritis), respiratory diseases, cardiovasculardiseases. In other embodiments, the compounds of the invention aresuitable for use in the treatment of diseases and disorders associatedwith fatty acid metabolism, including obesity and other metabolicdisorders.

In one embodiment, a method for the treatment of paroxysmal nocturnalhemoglobinuria (PNH) is provided that includes the administration of aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier. In another embodiment, a method for the treatment ofage-related macular degeneration (AMD) is provided that includes theadministration of an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In another embodiment, a method forthe treatment of rheumatoid arthritis is provided that includes theadministration of an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In another embodiment, a method forthe treatment of multiple sclerosis is provided that includes theadministration of an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In another embodiment, a method forthe treatment of myasthenia gravis is provided that includes theadministration of an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In another embodiment, a method forthe treatment of atypical hemolytic uremic syndrome (aHUS) is providedthat includes the administration of an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, optionally ina pharmaceutically acceptable carrier. In another embodiment, a methodfor the treatment of C3 glomerulonephritis is provided that includes theadministration of an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In another embodiment, a method forthe treatment of abdominal aortic aneurysm is provided that includes theadministration of an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In another embodiment, a method forthe treatment of neuromyelitis optica (NMO) is provided that includesthe administration of an effective amount of a compound of Formula I, ora pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In some embodiments, the present invention provides methods of treatingor preventing an inflammatory disorder or a complement related disease,by administering to a host in need thereof an effective amount of acompound of Formula I of the invention. In some embodiments, the presentinvention provides methods of treating or preventing an inflammatorydisorder more generally, an immune disorder, autoimmune disorder, orcomplement factor D related disease, by providing an effective amount ofa compound or pharmaceutically acceptable salt of Formula I to patientwith a factor D mediated inflammatory disorder. A compound or salt ofFormula I may be provided as the only active agent or may be providedtogether with one or more additional active agents.

In one embodiment, a method for the treatment of a disorder associatedwith a dysfunction in the complement cascade is provided that includesthe administration of an effective amount of a compound of Formula I, ora pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In one embodiment, a method ofinhibiting activation of the alternative complement pathway in a subjectis provided that includes the administration of an effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof,optionally in a pharmaceutically acceptable carrier. In one embodiment,a method of modulating factor D activity in a subject is provided thatincludes the administration of an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, optionally ina pharmaceutically acceptable carrier.

“Prevention” as used in this disclosure means decreasing the likelihoodof the appearance of symptoms in a patient administered the compoundprophylactically as compared to the likelihood of the appearance ofsymptoms in patients not administered the compound or decreasing theseverity of symptoms in a patient administered the compoundprophylactically as compared to the severity of symptoms experienced bypatients with the disorder or condition who were not administered thecompound. In an alternative embodiment, an effective amount of acompound of Formula I is used to prevent or prophylaxis of a complementfactor D related disorder.

An effective amount of a pharmaceutical composition/combination of theinvention may be an amount sufficient to (a) inhibit the progression ofa disorder mediated by the complement pathway, including aninflammatory, immune, including an autoimmune, disorder or complementfactor D related disease; (b) cause a regression of an inflammatory,immune, including an autoimmune, disorder or complement factor D relateddisease; or (c) cause a cure of an inflammatory, immune, including anautoimmune, disorder or complement factor D related disease.

An effective amount of a compound or pharmaceutical compositiondescribed herein will also provide a sufficient amount of the activeagent when administered to a patient to provide a clinical benefit. Suchan amount may be ascertained experimentally, for example by assayingblood concentration of the agent, or theoretically, by calculatingbioavailability.

V. Combination Therapy

In one embodiment, a compound or salt of Formula I may be provided incombination or alternation with at least one additional inhibitor of thecomplement system or a second active compound with a differentbiological mechanism of action. In one embodiment, a compound or salt ofFormula I may be provided in combination with a complement C5 inhibitoror C5 convertase inhibitor. In another embodiment, a compound or salt ofFormula I may be provided in combination with eculizumab. In oneembodiment, a compound or salt of Formula I may be provided incombination with additional inhibitors of factor D.

In one embodiment, a compound or salt of Formula I may be providedtogether with a compound that inhibits an enzyme that metabolizesprotease inhibitors. In one embodiment, a compound or salt of Formula Imay be provided together with ritonavir.

In nonlimiting embodiments, a compound or salt of Formula I may beprovided together with a protease inhibitor, a soluble complementregulator, a therapeutic antibody (monoclonal or polyclonal), complementcomponent inhibitors, receptor agonists, or siRNAs.

Nonlimiting examples of active agents in these categories are:

Protease inhibitors: plasma-derived C1-INH concentrates, for exampleCetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma), and Cinryze®;and recombinant human C1-inhibitors, for example Rhucin®;

Soluble complement regulators: Soluble complement receptor 1 (TP10)(Avant Immunotherapeutics); sCR1-sLex/TP-20 (Avant Immunotherapeutics);MLN-2222/CAB-2 (Millenium Pharmaceuticals); Mirococept (InflazymePharmaceuticals);

Therapeutic antibodies: Eculizumab/Soliris (Alexion Pharmaceuticals);Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234(Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (GenmabA/S);

Complement component inhibitors: Compstatin/POT-4 (PotentiaPharmaceuticals); ARC1905 (Archemix);

Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717(Jerini);

Others: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals).

In an embodiment, the present invention provides a method of treating orpreventing age-related macular degeneration (AMD) by administering to asubject in need thereof an effective amount of a composition comprisinga compound of the current invention. In one embodiment, the compositionsof the present invention are administered in combination with ananti-VEGF agent. Nonlimiting examples of anti-VEGF agents include, butare not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals);ranibizumab (Lucentis®: Genentech and Novartis); and pegaptanib(Macugen®; OSI Pharmaceuticals and Pfizer); Bevacizumab (Avastin;Genentech/Roche); anecortane acetate, squalamine lactate, andcorticosteroids, including, but not limited to, triamcinolone acetonide.

In another embodiment, a compound of Formula I can be combined with asecond agent in order to treat a disorder of the eye.

Examples of types of therapeutic agents that can be used in combinationfor ocular applications include anti-inflammatory drugs, antimicrobialagents, anti-angiogenesis agents, immunosuppressants, antibodies,steroids, ocular antihypertensive drugs and combinations thereof.Examples of therapeutic agents include amikacin, anecortane acetate,anthracenedione, anthracycline, an azole, amphotericin B, bevacizumab,camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidinedigluconate, clortrimazole, a clotrimazole cephalosporin,corticosteroids, dexamethasone, desamethazone, econazole, eftazidime,epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines,fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itraconazole,ivermectin, ketoconazole, levofloxacin, macrolides, miconazole,miconazole nitrate, moxifloxacin, natamycin, neomycin, nystatin,ofloxacin, polyhexamethylene biguanide, prednisolone, prednisoloneacetate, pegaptanib, platinum analogues, polymicin B, propamidineisethionate, pyrimidine nucleoside, ranibizumab, squalamine lactate,sulfonamides, triamcinolone, triamcinolone acetonide, triazoles,vancomycin, anti-vascular endothelial growth factor (VEGF) agents, VEGFantibodies, VEGF antibody fragments, vinca alkaloid, timolol, betaxolol,travoprost, latanoprost, bimatoprost, brimonidine, dorzolamide,acetazolamide, pilocarpine, ciprofloxacin, azithromycin, gentamycin,tobramycin, cefazolin, voriconazole, gancyclovir, cidofovir, foscarnet,diclofenac, nepafenac, ketorolac, ibuprofen, indomethacin,fluoromethalone, rimexolone, anecortave, cyclosporine, methotrexate,tacrolimus and combinations thereof. Examples of eye disorders that maybe treated according to the compositions and methods disclosed hereininclude amoebic keratitis, fungal keratitis, bacterial keratitis, viralkeratitis, onchorcercal keratitis, bacterial keratoconjunctivitis, viralkeratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelialdystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dryeye diseases, environmental dry eye diseases, corneal neovascularizationdiseases, post-corneal transplant rejection prophylaxis and treatment,autoimmune uveitis, infectious uveitis, anterior uveitis, posterioruveitis (including toxoplasmosis), pan-uveitis, an inflammatory diseaseof the vitreous or retina, endophthalmitis prophylaxis and treatment,macular edema, macular degeneration, age related macular degeneration,proliferative and non-proliferative diabetic retinopathy, hypertensiveretinopathy, an autoimmune disease of the retina, primary and metastaticintraocular melanoma, other intraocular metastatic tumors, open angleglaucoma, closed angle glaucoma, pigmentary glaucoma and combinationsthereof.

A compound of Formula I, or a combination of Formula I and anotheractive agent, can be administered into an eye compartment of viainjection into the vitreous chamber, subretinal space, subchoroidalspace, the episclera, the conjunctiva, the sclera, the anterior chamber,and the cornea and compartments therein (e.g., subepithelial,intrastromal, endothelial).

In an alternative embodiment, a compound of Formula I, or a combinationof Formula I and another active agent, can be administered into an eyecompartment via binding to a mucosal penetrating particle to treat acondition located in the vitreous chamber, subretinal space,subchoroidal space, the episclera, the conjunctiva, the sclera or theanterior chamber, and the cornea and compartments therein (e.g.,subepithelial, intrastromal, endothelial). Mucosal penetrating particlesare known in the art, and are described in, for example, PCT publishedapplication WO 2013166436 to Kala Pharmaceuticals, incorporated in itsentirety herein.

In other embodiments, a composition comprising compound of Formula Isuitable for topical administration to an eye is provided. Thepharmaceutical composition comprises a plurality of coated particles,comprising a core particle comprising a compound of Formula I, whereinFormula I constitutes at least about 80 wt % of the core particle, and acoating comprising one or more surface-altering agents, wherein the oneor more surface-altering agents comprise at least one of a poloxamer, apoly(vinyl alcohol), or a polysorbate. The one or more surface-alteringagents is present on the outer surface of the core particle at a densityof at least 0.01 molecules/nm. The one or more surface-altering agentsis present in the pharmaceutical composition in an amount of betweenabout 0.001% to about 5% by weight. The plurality of coated particleshave an average smallest cross-sectional dimension of less than about 1micron. The pharmaceutical composition also includes one or moreophthalmically acceptable carriers, additives, and/or diluents.

It will be appreciated by one of ordinary skill in the art thatparticles suitable for use with the presently disclosed methods canexist in a variety of shapes, including, but not limited to, spheroids,rods, disks, pyramids, cubes, cylinders, nanohelixes, nanosprings,nanorings, rod-shaped particles, arrow-shaped particles, teardrop-shapedparticles, tetrapod-shaped particles, prism-shaped particles, and aplurality of other geometric and non-geometric shapes. In someembodiments, the presently disclosed particles have a spherical shape.

In one embodiment, the present invention provides a method of treatingor preventing paroxysmal nocturnal hemoglobinuria (PNH) by administeringto a subject in need thereof an effective amount of a compositioncomprising a compound of the current invention. In one embodiment, thepresent invention provides a method of treating or preventing paroxysmalnocturnal hemoglobinuria (PNH) by administering to a subject in needthereof an effective amount of a composition comprising a compound ofthe current invention in combination or alternation with additionalinhibitors of the complement system or another active compound with adifferent biological mechanism of action. In another embodiment, thepresent invention provides a method of treating or preventing paroxysmalnocturnal hemoglobinuria (PNH) by administering to a subject in needthereof an effective amount of a composition comprising a compound ofthe current invention in combination or alternation with eculizumab.

In one embodiment, the present invention provides a method of treatingor preventing rheumatoid arthritis by administering to a subject in needthereof an effective amount of a composition comprising a compound ofthe current invention. In one embodiment, the present invention providesa method of treating or preventing rheumatoid arthritis by administeringto a subject in need thereof an effective amount of a compositioncomprising a compound of the current invention in combination oralternation with an additional inhibitor of the complement system. Inanother embodiment, the present invention provides a method of treatingor preventing rheumatoid arthritis by administering to a subject in needthereof an effective amount of a composition comprising a compound ofthe current invention in combination or alternation with methotrexate.

In certain embodiments, a compound of Formula I is administered incombination or alternation with at least one anti-rhuematoid arthritisdrug selected from: salicylates including aspirin (Anacin, Ascriptin,Bayer Aspirin, Ecotrin) and salsalate (Mono-Gesic, Salgesic);nonsteroidal anti-inflammatory drugs (NSAIDs); nonselective inhibitorsof the cyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac(Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis),naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine),indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam(Mobic); selective cyclo-oxygenase-2 (COX-2) inhibitors includingCelecoxib (Celebrex); disease-modifying antirheumatic drugs (DMARDs),including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), goldsalts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine(Plaquenil), leflunomide (Arava), methotrexate (Rheumatrex),penicillamine (Cuprimine), and sulfasalazine (Azulfidine); biologicdrugs including abatacept (Orencia), etanercept (Enbrel), infliximab(Remicade), adalimumab (Humira), and anakinra (Kineret); corticosteroidsincluding betamethasone (Celestone Soluspan), cortisone (Cortone),dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol),prednisolone (Delta-Cortef), prednisone (Deltasone, Orasone), andtriamcinolone (Aristocort); gold salts, including Auranofin (Ridaura);Aurothioglucose (Solganal); Aurolate; Myochrysine; or any combinationthereof.

In one embodiment, the present invention provides a method of treatingor preventing multiple sclerosis by administering to a subject in needthereof an effective amount of a composition comprising a compound ofthe current invention. In one embodiment, the present invention providesa method of treating or preventing multiple sclerosis by administeringto a subject in need thereof an effective amount of a compositioncomprising a compound of the current invention in combination oralternation with additional inhibitors of the complement system. Inanother embodiment, the present invention provides a method of treatingor preventing multiple sclerosis by administering to a subject in needthereof an effective amount of a composition comprising a compound ofthe current invention in combination or alternation with acorticosteroid. Examples of corticosteroids include, but are not limitedto, prednisone, dexamethasone, solumedrol, and methylprednisolone.

In one embodiment, a compound of Formula I is combined with at least oneanti-multiple sclerosis drug selected from: Aubagio (teriflunomide),Avonex (interferon beta-1a), Betaseron (interferon beta-1b), Copaxone(glatiramer acetate), Extavia (interferon beta-1b), Gilenya(fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone),Plegridy (peginterferon beta-1a), Rebif (interferon beta-1a), Tecfidera(dimethyl fumarate), Tysabri (natalizumab), Solu-Medrol (methylprednisolone), High-dose oral Deltasone (prednisone), H.P. Acthar Gel (ACTH),and combinations thereof.

In one aspect, a compound or salt of Formula I may be provided incombination or alternation with an immunosuppressive agent or ananti-inflammatory agent.

In one embodiment of the present invention, a compound described hereincan be administered in combination or alternation with at least oneimmunosuppressive agent. The immunosuppressive agent as nonlimitingexamples, may be a calcineurin inhibitor, e.g. a cyclosporin or anascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus),pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof,e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus,zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus,azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod oran analogue thereof, an anti IL-8 antibody, mycophenolic acid or a saltthereof, e.g. sodium salt, or a prodrug thereof, e.g. MycophenolateMofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig,anti-CD₂₅, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®),mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981(pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g,etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®),infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®),Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab,Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate,benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin,aspirin and ibuprofen.

Examples of anti-inflammatory agents include methotrexate,dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate,fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate,medrysone, prednisolone acetate, prednisolone sodium phosphate,difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate,lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam,meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenacsodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac,flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib,glucocorticoids, diclofenac, and any combination thereof. In oneembodiment, a compound of Formula I is combined with one or morenon-steroidal anti-inflammatory drugs (NSAIDs) selected from naproxensodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin(Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam(Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic),naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine(Toradol), naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren),and combinations thereof.

VI. Process of Preparation of Compounds of Formula I Abbreviations

(Boc)₂O di-tert-butyl dicarbonate

ACN Acetonitrile

ACOET, ETOAC ethyl acetate

CH₃OH, MeOH Methanol

CsF Cesium fluorideCuI Cuprous iodideDCM, CH₂Cl₂ Dichloromethane

DIEA, DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMFN,N-dimethylformamide DMSO Dimethylsulfoxide

DPPA diphenyl phosphoryl azide

Et₃N, TEA Triethylamine

EtOAc Ethyl acetateHATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate^(i)Pr₂NEt N,N-diisopropylethylamineK₂CO₃ Potassium carbonateNa₂SO₄ Sodium sulfateNaCl Sodium chlorideNaH Sodium hydrideNaHCO₃ Sodium bicarbonate

NEt₃ Trimethylamine

Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II)Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium(II) dichloridePd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)RT Room temperaturetBuOK potassium tert-butoxide

TEA Trimethylamine

Tf₂O trifluoromethanesulfonic anhydrideTFA Trifluoroacetic acid

THF Tetrahydrofuran TMSBr Bromotrimethylsilane

t_(R) Retention time

General Methods

All nonaqueous reactions were performed under an atmosphere of dry argonor nitrogen gas using anhydrous solvents. The progress of reactions andthe purity of target compounds were determined using one of the twoliquid chromatography (LC) methods listed below. The structure ofstarting materials, intermediates, and final products was confirmed bystandard analytical techniques, including NMR spectroscopy and massspectrometry.

LC Method A

-   -   Instrument: Waters Acquity Ultra Performance LC    -   Column: ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 μm    -   Column Temperature: 40° C.    -   Mobile Phase: Solvent A: H₂O+0.05% FA; Solvent B: CH₃CN+0.05% FA    -   Flow Rate: 0.8 mL/min    -   Gradient: 0.24 min @ 15% B, 3.26 min gradient (15-85% B), then        0.5 min @ 85% B.    -   Detection: UV (PDA), ELS, and MS (SQ in EI mode)

LC Method B

-   -   Instrument: Shimadzu LC-2010A HT    -   Column: Athena, C18-WP, 50×4.6 mm, 5 m    -   Column Temperature: 40° C.    -   Mobile Phase: Solvent A: H₂O/CH₃OH/FA=90/10/0.1; Solvent B:        H₂O/CH₃OH/FA=10/90/0.1    -   Flow Rate: 3 mL/min    -   Gradient: 0.4 min @ 30% B, 3.4 min gradient (30-100% B), then        0.8 min @ 100% B    -   Detection: UV (220/254 nm)

Example 1. General Route of Synthesis

A compound of the present invention can be prepared, for example, from acentral core. In one embodiment, for example, the central core Structure1 is an N-protected aminoacid where X¹ is nitrogen and PG=protectinggroup. In one embodiment, the central core is coupled to an amine togenerate an amide of Structure 2 (wherein L-B includes a C(O)N moiety).Structure 2 can then be deprotected to generate Structure 3. Structure 3is coupled to Structure 4 (A-COOH) to generate a second amide bond,forming a compound within Formula I. The chemistry is illustrated inRoute 1.

In an alternative embodiment, central core Structure 5 is reacted with aheterocyclic or heteroaryl compound to generate a compound of Structure6. In one embodiment, Structure 6 is deprotected to generate acarboxylic acid, Structure 7. In one embodiment, Structure 7 is coupledto an amine to generate a compound of Formula I. This chemistry isillustrated in Route 2.

In an alternative embodiment, Structure 8 is deprotected to generate anamine which is Structure 9. Structure 9 is then coupled to generate anamide which is Structure 6. Structure 6 is then deprotected to generatea carboxylic acid which is Structure 7. Structure 7 is then coupled toform the amide which falls within Formula I. The chemistry isillustrated in Route 3.

In an alternate embodiment, a heteroaryl or aryl moiety, 4-1, is coupledto a central core to generate 4-2. The protected acid, 4-2 is deblockedto form the carboxylic acid, 4-3. The carboxylic acid is then coupled toform an amide (L-B) which is 4-4. The heteroaryl or aryl moiety, A′, canthen be further derivitized to add substituents at the X¹¹, X¹², X¹³ andX¹⁴ positions to generate compounds of Formula I. This chemistry isillustrated in Route 4.

In an alternate embodiment, Structure 5-1 is coupled to an acid,Structure 5-2, to generate Structure 5-3. The carboxylic acid, Structure5-3, is deblocked to generate a carboxylic acid which is Structure 5-4.Carboxylic acid Structure 5-4 is coupled to an amine to form the productamide (L-B) which is a compound within Formula I. This chemistry isillustrated in Route 5.

In an alternate embodiment, Structure 6-1 is coupled to an amine togenerate an amide (L-B) which is Structure 6-2. Structure 6-2 is coupledto an amine to generate compounds within Formula I. This chemistry isillustrated in Route 6.

Example 2. Examples of Central Synthons

Z^(a) is halogen.

In one embodiment, deuterated L-proline synthons are disclosed.Deuterated synthons include, but are not limited to, for example, thefollowing compounds:

Structure A can be treated with deuterium oxide to generate Structure B.See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655;Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO2014/037480 (p. 103). Structure B can be reduced to generate StructureC. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655;Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. StructureC can be treated with Mitsunobu reaction conditions to generateStructure D. Structure B can be treated with DAST to generate StructureE. See, WO 2014/037480. Structure A can be treated with sodiumborodeuteride to generate Structure F. See, Dormoy, J.-R.; Castro, B.Synthesis 1986, 81-82. Compound F can be used to generate Structure K.See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82. Structure B can betreated with a deuterated reducing agent, for example sodiumborodeuteride to generate Structure G. Structure G can be treated withDAST to generate Structure H. Structure F can be used to generateStructure K. See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82.Structure G can be used to generate Structure I. Structure J can beprepared according to Hruby, V. J. et al. J. Am. Chem. Soc. 1979, 101,202-212. Structures A-J can be used to prepare compounds of Formula I.

Example 3. Preparation of Central-L-B Synthons

In Route 1a, 5-azaspiro[2.4]heptane-4,5-dicarboxylic acid,5-(1,1-dimethylethyl) ester, (4S)-, CAS 209269-08-9, can be prepared asdescribed in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8,1139-1144. In Step 2, the protected azaspiro[2.4]heptane is coupled toan amine in the presence of an organic solvent, a base and a couplingreagent to generate an amide bond; the L-B moiety. In one embodiment,the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment,the organic solvent is DMF. In one embodiment, the base isdiisopropylethylamine. In one embodiment, the coupling reagent is HATU.In Step 3, the protecting group is removed. In one embodiment, thestarting material is reacted with an acid in the presence of an organicsolvent. In one embodiment, the acid is 4N hydrochloric acid. In oneembodiment, the organic solvent is dioxane.

In Route 1b, (4S) 4-oxazolidinecarboxylic acid, hydrochloride is treatedwith an amine protecting reagent. In one embodiment, the amineprotecting reagent is di-tert-butyl dicarbonate. In another embodiment,3,4-oxazolidinedicarboxylic acid, 3-(1,1-dimethylethyl) ester, (4S)-, iscommercially available from JPM2 Pharmaceuticals. In one embodiment thereaction is carried out in an organic solvent in the presence of a base.In one embodiment, the organic solvent is acetonitrile. In oneembodiment, the base is 4-dimentylaminopyridine (DMAP). In Step 2, theprotected 4-oxazolidinecarboxylic acid is coupled to an amine in thepresence of an organic solvent, a base and a coupling reagent togenerate an amide bond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 3, the protectinggroup is removed. In one embodiment, the starting material is reactedwith an acid in the presence of an organic solvent. In one embodiment,the acid is 4N hydrochloric acid. In one embodiment, the organic solventis dioxane.

In Route 1c,(S)-5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-6-caboxylic acid, CAS1129634-44-1, is commercially available from Ark Pharm. In Step 2, thecarboxylic acid is coupled to an amine in the presence of an organicsolvent, a base and a coupling reagent to generate an amide bond; theL-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the base is diisopropylethylamine. In one embodiment, thecoupling reagent is HATU. In Step 3, the protecting group is removed. Inone embodiment, the starting material is reacted with an acid in thepresence of an organic solvent. In one embodiment, the acid is 4Nhydrochloric acid. In one embodiment, the organic solvent is dioxane.

In Route 2a, commercially available Boc-L-proline is coupled to an aminein the presence of an organic solvent, a base and a coupling reagent togenerate an amide bond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 2, the Bocprotecting group is removed. In one embodiment, the starting material isreacted with an acid in the presence of an organic solvent. In oneembodiment, the acid is 4N hydrochloric acid. In one embodiment, theorganic solvent is dioxane.

In Route 2b, commercially available (1R, 3S,5R)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, from Enamine, is coupled to an amine in the presence of an organicsolvent, a base and a coupling reagent to generate an amide bond; theL-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the base is diisopropylethylamine. In one embodiment, thecoupling reagent is HATU. In Step 2, the Boc protecting group isremoved. In one embodiment, the starting material is reacted with anacid in the presence of an organic solvent. In one embodiment, the acidis 4N hydrochloric acid. In one embodiment, the organic solvent isdioxane.

In Route 2c, commercially available(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid,from Manchester Organics, is coupled to an amine in the presence of anorganic solvent, a base and a coupling reagent to generate an amidebond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 2, the Bocprotecting group is removed. In one embodiment, the starting material isreacted with an acid in the presence of an organic solvent. In oneembodiment, the acid is 4N hydrochloric acid. In one embodiment, theorganic solvent is dioxane.

In Route 2d, commercially available(S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid, from Chem-Impex,is coupled to an amine in the presence of an organic solvent, a base anda coupling reagent to generate an amide bond; the L-B moiety. In oneembodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In oneembodiment, the organic solvent is DMF. In one embodiment, the base isdiisopropylethylamine. In one embodiment, the coupling reagent is HATU.In Step 2, the Boc protecting group is removed. In one embodiment, thestarting material is reacted with an acid in the presence of an organicsolvent. In one embodiment, the acid is 4N hydrochloric acid. In oneembodiment, the organic solvent is dioxane. This chemistry isillustrated in Scheme 2.

Additional starting materials that can readily be converted toCentral-L-B-Synthons include, but are not limited to:(S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid,CAS 90104-21-5, available from Ark Pharm;cyclopent-1-ene-1,2-dicarboxylic acid, CAS 3128-15-2, purchased from ArkPharm; imidazole, 1H-imidazole-1,2-dicarboxylic acid,1-(1,1-dimethylethyl) 2-ethyl ester, CAS 553650-00-3, commerciallyavailable from FCH Group; Boc-L-octahydroindole-2-carboxylic acid can bepurchased from Chem Impex. The compound,

can be prepared according to the procedures disclosed in WO 2004/111041;(S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the AldrichChemical Co.;(1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]hexane-2-carboxylicacid is available from Ark Pharm; (S)-3-Boc-thiazolidine-2-carboxylicacid is available from Alfa Aesar;(2S,4R)-1-(tert-butoxycarbonyl)-4-chloropyrrolidine-2-carboxylic acid isavailable from Arch Bioscience;(1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylicacid is available from Ark Pharm; 1,2-pyrrolidinedicarboxylic acid,3-[[(phenylmethoxy)carbonyl]amino]-, 1-(1,1-dimethylethyl) ester,(2S,3R) can be prepared as disclosed in WO 2004/007501. The Cbz groupcan be removed and the amino group can be alkylated to generate centralcore compounds of the present invention.

The compound

can be prepared as disclosed by Braun, J. V.; Heymons, Albrecht Berichteder Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930)63B, 502-7.

The compounds (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester and(2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester can be prepared as a mixture according to WO2012/093101 to Novartis and the regioisomers can be ultimately separatedonce coupled to generate the central core-L-B synthons. The compound(S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the AldrichChemical Co.

Example 4. Preparation of Alkynyl Synthons

Alkynyl synthons include but are not limited to:

wherein

R³⁰ is independently chosen at each occurrence from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S; (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S; COOH, Si(CH₃)₃, COOR^(30a), C₂-C₆alkanoyl,—B(OH)₂, —C(O)(CH₂)₁₋₄S(O)R²¹, —P(O)(OR²¹)(OR²²), —P(O)(OR²¹)R²²,—P(O)R²¹R²², —NR⁹P(O)(NHR²¹)(NHR²²), —NR⁹P(O)(OR²¹)(NHR²²),—NR⁹P(O)(OR²¹)(OR²²), —C(S)R²¹, —NR²¹SO₂R²², —NR⁹S(O)NR⁰R²²,—NR⁹SO₂NR¹⁰R²², —SO₂NR⁹COR²², —SO₂NR⁹CONR²¹R²², —NR²¹SO₂R²²,—C(O)NR²¹SO₂R²², —C(NIH2)NR⁹R²², —C(NH₂)NR⁹S(O)₂R²², —NR⁹C(O)OR¹⁰,—NR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², —C(O)R²⁴R²⁵, —NR⁹C(O)R²¹, —C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR²⁴R²⁵, —(CH₂)₁₋₄OC(O)R²¹, each of which R³⁰can be optionally substituted;

R^(30a) is C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl-, (aryl)C₀-C₄alkyl-, (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl- having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S, each of which R^(30a) can be optionallysubstituted.

Alkyne synthons can be prepared and coupled by a person skilled in theart. For example, Amashiro discloses alkynyl amines in WO 2008/047831.Aryl alkynes are disclosed in Tang, T. et al., J. Org. Chem., 2013, 78,3170-3175. Alkynes can be synthesized from primary alcohols; see,Quesada, R. and Taylor, R. J. K., Tett. Lett., 2005, 46, 6473-6476.Alkynes can be synthesized from aldehydes using an in situ preparationof dimethyldiazomethylphosphonate; see Roth, G. J. et al., Synthesis,2004, 59-62. Bromoalkenes can be converted to alkynes; see, Okutani, M.and Mori, Y., J. Org. Chem., 2009, 74, 442-444. (Z)-1-Bromoalkenes canbe converted to alkynes; see, Kuang, C., et al., Tetrahedron, 2005, 61,4043-4052.

Example 5. Preparation of A-C(O)— Moiety

In Step 1 of Route 5a, the stating material is treated with an organicsolvent, an acylating reagent and a catalyst to add the R⁶ substitutent.In one embodiment, the organic solvent is toluene. In one embodiment,the acylating reagent is acetyl chloride. In one embodiment, thecatalyst is tin tetrachloride. In another embodiment, the startingmaterial in Step 1 is treated with an inorganic cyanide andorganometallic catalyst to generate a cyano group at the R⁶ position.The cyano group is treated with a oxime to generate an amide at the R⁶position. In Step 2, the nitrogen of the heteroaryl ring is treated witha tert-butyl haloacetate, an organic solvent and a base. In oneembodiment, the halo group, LG₂, is bromine. In one embodiment, theorganic solvent is acetonitrile. In one embodiment, the base ispotassium carbonate. In Step 3, the tert-butyl ester is treated with anorganic acid and an organic solvent to generate an acid. In oneembodiment, the organic acid is trifluoroacetic acid. In one embodiment,the organic solvent is dichloromethane. This chemistry is illustrated inRoute 5a.

In Step 1 of Route 5b, the stating material is treated with an organicsolvent, an acylating reagent and a catalyst to add the R⁶ substitutent.In one embodiment, the organic solvent is toluene. In one embodiment,the acylating reagent is acetyl chloride. In one embodiment, thecatalyst is tin tetrachloride. In another embodiment, the startingmaterial in Step 1 is treated with an inorganic cyanide andorganometallic catalysts to add a cyano group at the R⁶ position. Thecyano group is treated with an oxime to generate an amide at the R⁶position. In Step 2, the nitrogen of the heteroaryl ring is treated witha tert-butyl haloacetate, an organic solvent and a base. In oneembodiment, the halo group, LG₂, is bromine. In one embodiment, theorganic solvent is acetonitrile. In one embodiment, the base ispotassium carbonate. In Step 3, the tert-butyl ester is treated with anorganic acid and an organic solvent to generate a carboxylic acid. Inone embodiment, the organic acid is trifluoroacetic acid. In oneembodiment, the organic solvent is dichloromethane. This chemistry isillustrated in Route 5b.

Example 6: Coupling of Central-L-B Synthons to —C(O)— Moieties

As illustrated in Scheme 6a, central-LB synthons and a carboxylic acid(C(O)-A) are combined and treated with an organic solvent, a base, andcoupling agent. In one embodiment, the solvent is DMF. In oneembodiment, the base is N,N-diisopropylethylamine. In one embodiment thecoupling reagent is(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate) (HATU).

As illustrated in Scheme 6b, the central-LB synthons and carboxylic acid(C(O)-A) are combined and treated with an organic solvent, a base, andcoupling agent. In one embodiment, the solvent is DMF. In oneembodiment, the base is N,N-diisopropylethylamine. In one embodiment thecoupling reagent is(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate) (HATU).

Example 7. Synthesis of Alkynes of Formula I

As an example, the proline derivative from Example 6 Scheme 6b istreated with two organometallic catalysts, trimethylsilylacetylene, abase and organic solvent at an elevated temperature to generate atrimethylsilyl protected alkyne. In one embodiment, the firstorganometallic catalyst is copper iodide. In one embodiment, the secondorganometallic catalyst is tetrakis(triphenylphosphine)palladium(0). Inone embodiment, the base is triethylamine. In one embodiment, theorganic solvent is DMF. In one embodiment, the reaction is deoxygenatedby bubbling argon into the pressure vessel. In one embodiment, thereaction is treated at an elevated temperature. In one embodiment, thereaction is treated at about 80 to about 105° C. In Step 2, thetrimethylsilyl protected akyne is treated with a fluoride reagent and anorganic solvent. In one embodiment, the fluoride reagent istetrabutylammonium fluoride. In one embodiment, the organic solvent istetrahydrofuran. In Step 3, the alkyne is treated with LG-R³⁰, twoorganometallic catalysts, a base, and an organic solvent at an elevatedtemperature. In one embodiment, the first organometallic catalyst iscopper iodide. In one embodiment, the second organometallic catalyst isbis(triphenylphosphine)palladium(II) dichloride. In one embodiment, thebase is triethylamine. In one embodiment, the organic solvent is DMF. Inone embodiment, the elevated temperature is at about 80 to about 95° C.In one embodiment the LG R³⁰ group is an heteroaryl halide. In oneembodiment, the LG-R³⁰ group is an aryl halide. This chemistry isillustrated in Scheme 7a.

In an alternate embodiment, the proline derivative from Example 6 Scheme6b is treated with two organometallic catalysts, an alkyne, a base andorganic solvent at an elevated temperature to generate an alkyne ofFormula I. In one embodiment, the first organometallic catalyst iscopper iodide. In one embodiment, the second organometallic catalyst istetrakis(triphenylphosphine)palladium(0). In one embodiment, the base istriethylamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the reaction is deoxygenated by bubbling argon into thepressure vessel. In one embodiment, the reaction is treated at anelevated temperature. In one embodiment, the reaction is treated atabout 80 to about 105° C.

The proline derivative from Example 6 Scheme 6b is treated with twoorganometallic catalysts, trimethylsilylacetylene, a base and organicsolvent at an elevated temperature to generate a trimethylsilylprotected alkyne. In one embodiment, the first organometallic catalystis copper iodide. In one embodiment, the second organometallic catalystis tetrakis(triphenylphosphine)palladium(0). In one embodiment, the baseis triethylamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the reaction is deoxygenated by bubbling argon into thepressure vessel. In one embodiment, the reaction is treated at anelevated temperature. In one embodiment, the reaction is treated atabout 80 to about 105° C. In Step 2, the trimethylsilyl protected akyneis treated with a fluoride reagent and an organic solvent. In oneembodiment, the fluoride reagent is tetrabutylammonium fluoride. In oneembodiment, the organic solvent is tetrahydrofuran. In Step 3, thealkyne is treated with LG-R³⁰, two organometallic catalysts, a base, andan organic solvent at an elevated temperature. In one embodiment, thefirst organometallic catalyst is copper iodide. In one embodiment, thesecond organometallic catalyst is bis(triphenylphosphine)palladium(II)dichloride. In one embodiment, the base is triethylamine. In oneembodiment, the organic solvent is DMF. In one embodiment, the elevatedtemperature is at about 80 to about 95° C. In one embodiment the LG R³⁰group is an heteroaryl halide. In one embodiment, the LG-R³⁰ group is anaryl halide. This chemistry is illustrated in Scheme 7b.

In an alternate embodiment, the proline derivative from Example 6 Scheme6b is treated with two organometallic catalysts, an alkyne, a base andorganic solvent at an elevated temperature to generate an alkyne ofFormula I. In one embodiment, the first organometallic catalyst iscopper iodide. In one embodiment, the second organometallic catalyst istetrakis(triphenylphosphine)palladium(0). In one embodiment, the base istriethylamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the reaction is deoxygenated by bubbling argon into thepressure vessel. In one embodiment, the reaction is treated at anelevated temperature. In one embodiment, the reaction is treated atabout 80 to about 105° C.

In an alternative embodiment, a TMS alkyne from Example 7 Scheme 7a or7b can be treated with an inorganic fluoride, an organic solvent andcarbon dioxide to generate a carboxylic acid. In one embodiment, theinorganic fluoride is cesium fluoride. In one embodiment, the organicsolvent is dimethyl sulfoxide. The resulting carboxylic acid can betreated with a sulfonamide anion to generate a compound of Formula I.

Example 8. Synthesis of 1A. (2S,4R)-tert-butyl2-((3-chloro-2-fluoro-benzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(2.33 gm, 10 mmol) was dissolved in DMF (50 ml) and ^(i)Pr₂NEt (8.6 ml,5 eq.) was added, followed by the addition of (3-chloro-2-fluorophenyl)methanamine (3.18 gm 20 mmol) at 5° C. Then HATU (8 gm, 2.1 eq) wasadded slowly at same temperature. The reaction mixture was then stirredfor 18 h at RT. After completion of the reaction monitored by HPLC, Thereaction mixture was diluted with 1M citric acid solution (200 ml+NaClsolid 20 gm) and extracted with DCM (150 mL×2), the organic layer wasthen washed with an aqueous solution of NaHCO₃ (100 ml) and washed withwater (100 ml), brine (100 ml) and dried over Na₂SO₄ and concentratedunder reduced pressure. The remaining residue was purified by columnchromatography (eluted with DCM/EtOAc) to give (2S,4R)-tert-butyl2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.

1B.(2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (A)

(2S,4R)-tert-butyl2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(500 mg) was taken in 4N HCl dioxane (30 ml) and resulting reactionmixture was stirred at rt for 3 h. After completion of the reactionmonitored by HPLC solvent was removed under reduced pressure. Theresidue, A, was used for next reaction.

Example 9. Synthesis of(2S,4R)-1-(2-(3-acetyl-5-(pyrimidin-2-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide

1-(5-Bromo-1H-indol-3-yl)ethanone (2) was prepared from 5-bromoindoleaccording to the procedure published by MacKay et al. (MacKay, J. A.;Bishop, R.; Rawal, V. H. Org. Lett. 2005, 7, 3421-3424.)

A mixture of 3.9 g (16.4 mmol) of 1-(5-bromo-1H-indol-3-yl)ethanone,2.63 mL (18.02 mmol) of tert-butyl bromoacetate and 2.50 g (18.02 mmol)potassium carbonate in anhydrous acetonitrile (80 mL) was refluxed for 5h. The reaction mixture was then cooled to RT and the solvent wasremoved under reduced pressure. The residue was taken in 1:1 mixture ofCH₂Cl₂ and water (100 mL: 100 mL). The two layers were separated and theorganic layer was washed with water (2×100 mL). Finally, the organiclayer was dried (Na₂SO₄) and concentrated. The resulting residue wasstirred with 50 mL of heptane for 30 min., cooled in an ice bath andfiltered, washing the solid with cold heptane (10 mL). This creamcolored solid was dried under high vacuum to give 5.6 g of producttert-Butyl 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate.

4.5 g of tert-Butyl 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate wasstirred in 1:1 mixture of CH₂Cl₂-TFA (90 mL) at RT for 4 h. Thevolatiles were removed under reduced pressure. The residue was dissolvedin 45 mL of DMF. 4.16 g (13.4 mmol) of hydrochloride salt of 5 was addedto this solution, followed by 11 mL of N,N-diisopropylethylamine (63.7mmol). The reaction mixture was cooled in an ice bath and 5.82 g of(15.3 mmol) HATU was added. Following the addition of HATU, the coolingbath was removed and the reaction mixture was stirred overnight at RT.This reaction mixture was then poured in 450 mL of 1.0 M aq. citric acidsolution. The separated product was isolated by filtration and the solidwas washed thoroughly with water. This gray solid was dried under highvacuum to give 7.4 g of product(2S,4R)-1-(2-(3-Acetyl-5-bromo-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide.

A mixture of 1 g (1.8 mmol) of(2S,4R)-1-(2-(3-Acetyl-5-bromo-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide,0.419 g (0.36 mmol) of tetrakis(triphenylphosphine)palladium(0), 0.138 g0.72 mmol) of cuprous iodide in DMF (10 mL) was deoxygenated by bubblingargon in a pressure vessel. Triethylamine (2.53 mL, 18.1 mmol) and 2.56mL (18.1 mmol) of ethynyltrimethylsilane were added under argon. Thepressure vessel was capped and heated at 100° C. overnight. Then thereaction mixture was cooled to RT and the solvent was removed underreduced pressure. The residue was purified by column chromatography(silica gel, 0-2% MeOH in CH₂Cl₂) to give 0.56 g of(2S,4R)-1-(2-(3-Acetyl-5-((trimethylsilyl)ethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamideas a yellow solid.

To a solution of(2S,4R)-1-(2-(3-Acetyl-5-((trimethylsilyl)ethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(0.5 g, 1 mmol) in THF (5 mL) was added 1.5 mL of 1.0 Mtetrabutylammonium fluoride in THF at RT. The reaction mixture wasstirred for 1 h. The solvent was removed under reduced pressure and theresidue was purified by column chromatography (silica gel, 0-2% MeOH inCH₂Cl₂) to give 0.26 g of(2S,4R)-1-(2-(3-acetyl-5-ethynyl-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamideas a light yellow solid.

A mixture of 0.16 g (1.0 mmol) of 2-bromopyrimidine, 0.141 g (0.2 mmol)of PdCl₂(PPh₃)₂, 0.043 g (0.23 mmol) of cuprous iodide in DMF (4 mL) wasdeoxygenated by bubbling argon in a pressure vessel. Triethylamine (2.0mL) and 0.250 g (0.5 mmol) of(2S,4R)-1-(2-(3-Acetyl-5-ethynyl-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamidewere added under argon. The pressure vessel was capped and heated at100° C. overnight. Then the reaction mixture was cooled to RT and thesolvent was removed under reduced pressure. The residue was purified bycolumn chromatography (silica gel, 0-4.5% MeOH in CH₂Cl₂) to give 35 mgof the desired product(2S,4R)-1-(2-(3-acetyl-5-(pyrimidin-2-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamideas a light red solid. ¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer)δ: 1.99-2.18 (m, 1H), 2.46 (s, 3H), 3.92 (ddd, J=24.4, 12.4, 2.8 Hz,1H), 4.26 (dd, J=12.8, 20.8 Hz, 1H), 4.32 (dd, J=28.4, 6.0 Hz, 1H),4.39-4.49 (m, 2H), 5.24 (d, J=17.2 Hz, 1H), 5.45 (d, J=17.2 Hz, 1H),5.51 (d, J=52.8 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 7.23 (t, J=6.4 Hz, 1H),7.40-7.51 (m, 4H), 7.59 (d, J=8.4 Hz, 1H), 8.36 (s, 1H), 8.47 (d, J=0.8Hz, 1H), 8.61 (t, J=5.6 Hz, 1H), 8.85 (d, J=4.8 Hz, 2H). ³¹F NMR (376MHz, DMSO-d₆, 300 K): (major rotamer) δ: −121.7, −176.1. LC (method 1):t_(R)=1.73 min. LC/MS (EI) m/z: [M+H]⁺ calcd for C₃₀H₂₄ClF₂N₅O₃, 575.9;found, 576.4.

Example 10: Additional Syntheses of Non-Limiting Examples of AlkyneCompounds of Formula I Compound 2:3-(3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)propiolicacid

As shown in Scheme 1,(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(2a, 2.33 g) was dissolved in DMF (50 ml) and DIEA (8.6 ml) was added,followed by the addition of (3-chloro-2-fluorophenyl) methanamine (2b,3.18 gm) at 5° C. Then HATU (8 gm) was added slowly at same temperature.The reaction mixture was then stirred for 18 h at RT. After completionof the reaction monitored by HPLC, The reaction mixture was diluted with1M citric acid solution (200 ml+NaCl solid 20 gm) and extracted with DCM(150 mL×2), the organic layer was then washed with an aqueous solutionof NaHCO₃ (100 ml) and washed with water (100 ml), brine (100 ml) anddried over Na₂SO₄ and concentrated under reduced pressure. The remainingresidue was purified by column chromatography (eluent: DCM/EtOAc) togive (2S,4R)-tert-butyl2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(2c).

(2S,4R)-tert-butyl2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(500 mg) was taken in 4N HCl dioxane (30 ml) and resulting reactionmixture was stirred at RT for 3 h. After completion of the reaction,solvent was removed under reduced pressure. The residue, 2d, was usedfor next reaction.

As shown in scheme 2, 1-(6-Bromo-1H-indol-3-yl)ethanone (2f) wasprepared from 6-bromoindole (2e) according to the procedure published byMacKay et al. (MacKay, J. A.; Bishop, R.; Rawal, V. H. Org. Lett. 2005,7, 3421-3424.)

A mixture of 0.5 g of 1-(6-bromo-1H-indol-3-yl)ethanone, 0.35 mL oftert-butyl bromoacetate and 0.318 g potassium carbonate in anhydrousacetonitrile (10 mL) was refluxed for 5 h. The reaction mixture was thencooled to RT and diluted with dichloromethane. K₂CO₃ was filtered offand the filtrate was concentrated under reduced pressure. The residuewas purified by chromatography over silica gel (eluent: 0-25% EtOAc inhexanes) to get 0.7 g of white solid of tButyl2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (2g).

Compound 2e (31.0 g) was taken in 4.0 N HCl in dioxane and stirredovernight at RT. Then 150 mL of additional 4.0 N HCl in dioxane wasadded and stirred for 6 h at RT. The volatiles were then removed underreduced pressure and the residue was dried under high vacuum to get 25.3g of 2-(3-acetyl-6-bromo-1H-indol-1-yl)acetic acid (2h).

Compound 2h (25.3 g) was dissolved in 250 mL of DMF. 27.86 g ofhydrochloride salt of 2d was added to this solution, followed by 83.82mL of N,N-diisopropylethylamine. The reaction mixture was cooled in anice bath and 38.98 g of HATU was added. Following the addition of HATU,the cooling bath was removed and the reaction mixture was stirred for 1h at RT. This reaction mixture was then poured in 250 mL of 1.0 M aq.citric acid solution. The separated product was isolated by filtrationand the solid was washed thoroughly with water. This cream solid wasdried under high vacuum to give 48 g of product(2S,4R)-1-(2-(3-Acetyl-6-bromo-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(2i). This solid was then stirred with 250 mL of EtOAc for 30 min at RTand filtered, washing the solid with 60 mL of EtOAc to get 45 g of theproduct 2i.

A mixture of 0.8 g of(2S,4R)-1-(2-(3-Acetyl-6-bromo-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(2i), 0.669 g of Pd(PPh₃)₄, 0.124 g of cuprous iodide in DMF (8 mL) wasdeoxygenated by bubbling argon in a pressure vessel. Triethylamine (4mL), and 2.6 mL of ethynyltrimethylsilane were added under argon. Thepressure vessel was capped and heated at 100° C. overnight. Then thereaction mixture was cooled to RT and the solvent was removed underreduced pressure. The residue was purified by chromatography over silicagel (eluent: 0-2.5% MeOH in CH₂Cl₂) to give 0.68 g of(2S,4R)-1-(2-(3-Acetyl-6-((trimethylsilyl)ethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(2j) as orange yellow solid.

Synthesized following the procedure of Kobayashi et al (Kobayashi et al,Org. Biomol. Chem. 2013, 11, 3773-3775). A flask was charged with 96 mgof CsF in anhydrous DMSO (3 mL) under CO₂ atmosphere. Then 0.3 g of 2jwas added and stirred under CO₂ atmosphere in a balloon overnight at RT.The reaction mixture was diluted with water (30 mL) and extracted withdichloromethane. The aq. layer was acidified with aq. 6N HCl at 0° C.and extracted with EtOAc. Then the EtOAc layer was dried (Na₂SO₄) andconcentrated. The residue was purified by chromatography over silica gel(eluent: 0-3.2% MeOH in CH₂Cl₂) to get 75 mg of3-(3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)propiolicacid (2) as cream colored solid. ¹H NMR (400 MHz, DMSO-d₆, 300 K):(major rotamer) δ 2.05-2.18 (m, 1H), 2.45 (s, 3H), 2.50-2.58 (m, 1H),3.87-4.08 (m, 1H), 4.11-4.16 (m, 1H), 4.23-4.29 (m, 1H), 4.35-4.49 (m,2H), 5.25 (d, J=17.2 Hz, 1H), 5.45 (d, J=17.2 Hz, 1H), 5.52 (d, J=53.2Hz, 1H), 6.90 (t, J=8 Hz, 1H), 7.19 (t, J=6.8 Hz, 1H), 7.33-7.55 (m,2H), 7.91 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 8.61 (t, J=5.6Hz, 1H), 13.70 (brs, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆, 300 K): (majorrotamer) δ −121.8, −176.1. LC (method 1): t_(R)=1.53 min. LC/MS (EI)m/z: [M+H]⁺ calcd for C₂₇H₂₂ClF₂N₃O₅, 542; found, 542.

Compound 6:3-(3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)propiolicacid

Same procedure as for the synthesis of compound 2 was followed, exceptthe starting material was 5-bromoindole 6a.

1-(5-Bromo-1H-indol-3-yl)ethanone (6b) was prepared from 5-bromoindoleaccording to the procedure published by MacKay et al. (MacKay, J. A.;Bishop, R.; Rawal, V. H. Org. Lett. 2005, 7, 3421-3424.)

A mixture of 3.9 g of 1-(5-bromo-1H-indol-3-yl)ethanone, 2.63 mL oftert-butyl bromoacetate and 2.50 g potassium carbonate in anhydrousacetonitrile (80 mL) was refluxed for 5 h. The reaction mixture was thencooled to RT and the solvent was removed under reduced pressure. Theresidue was taken in 1:1 mixture of CH₂Cl₂ and water (100 mL: 100 mL).The two layers were separated and the organic layer was washed withwater (2×100 mL). Finally, the organic layer was dried (Na₂SO₄) andconcentrated. The resulting residue was stirred with 50 mL of heptanefor 30 min., cooled in an ice bath and filtered, washing the solid withcold heptane (10 mL). This cream colored solid was dried under highvacuum to give 5.6 g of product tert-Butyl2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (6c).

tert-Butyl 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (6c, 4.5 g) wasstirred in 1:1 mixture of CH₂Cl₂-TFA (90 mL) at RT for 4 h. Thevolatiles were removed under reduced pressure. The residue was dissolvedin 45 mL of DMF. 4.16 g (13.4 mmol) of hydrochloride salt of 2d wasadded to this solution, followed by 11 mL of N,N-diisopropylethylamine(63.7 mmol). The reaction mixture was cooled in an ice bath and 5.82 gof (15.3 mmol) HATU was added. Following the addition of HATU, thecooling bath was removed and the reaction mixture was stirred overnightat RT. This reaction mixture was then poured in 450 mL of 1.0 M aq.citric acid solution. The separated product was isolated by filtrationand the solid was washed thoroughly with water. This gray solid wasdried under high vacuum to give 7.4 g of product(2S,4R)-1-(2-(3-Acetyl-5-bromo-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(6e).

A mixture of 1 g of(2S,4R)-1-(2-(3-Acetyl-5-bromo-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(6e), 0.419 g of tetrakis(triphenylphosphine)palladium(0), 0.138 g ofcuprous iodide in DMF (10 mL) was deoxygenated by bubbling argon in apressure vessel. Triethylamine (2.53 mL) and 2.56 mL ofethynyltrimethylsilane were added under argon. The pressure vessel wascapped and heated at 100° C. overnight. Then the reaction mixture wascooled to RT and the solvent was removed under reduced pressure. Theresidue was purified by column chromatography over silica gel (eluent:0-2% MeOH in CH₂Cl₂) to give 0.56 g of(2S,4R)-1-(2-(3-acetyl-5-((trimethylsilyl)ethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(6f) as a yellow solid.

Synthesized following the procedure of Kobayashi et al (Kobayashi et al,Org. Biomol. Chem. 2013, 11, 3773-3775) as described for 2. A flask wascharged with 176 mg of CsF in anhydrous DMSO (5 mL) under CO₂atmosphere. Then 0.55 g of 6f was added and stirred under CO₂ atmospherein a balloon overnight at RT. The reaction mixture was diluted withwater (30 mL) and extracted with dichloromethane. The aq. layer wasacidified with aq. 6N HCl at 0° C. and extracted with EtOAc. Then theEtOAc layer was dried (Na₂SO₄) and concentrated. The residue was washedwith dichloromethane to get 130 mg of3-(3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)propiolicacid (6) as light orange solid. ¹H NMR (400 MHz, DMSO-d₆, 300 K): (majorrotamer) δ 2.05-2.18 (m, 1H), 2.45 (s, 3H), 2.49-2.58 (m, 1H), 3.84-3.97(m, 1H), 4.09-4.18 (m, 1H), 4.23-4.28 (m, 1H), 4.34-4.49 (m, 2H), 5.23(d, J=17.2 Hz, 1H), 5.43 (d, J=17.2 Hz, 1H), 5.50 (d, J=52.4 Hz, 1H),6.96 (t, J=7.6 Hz, 1H), 7.22 (t, J=6.4 Hz, 1H), 7.42-7.44 (m, 2H), 7.57(d, J=8.4 Hz, 1H), 8.36 (s, 1H), 8.44 (d, J=1.2 Hz, 1H), 8.59 (t, J=6Hz, 1H), 13.58 (brs, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆, 300 K): (majorrotamer) δ −121.7, −176.1. LC (method 1): t_(R)=1.26 min. LC/MS (EI)m/z: [M+H]⁺ calcd for C₂₇H₂₂ClF₂N₃O₅, 542; found, 542.

Compound 8:(2S,4R)-1-(2-(3-acetyl-5-(3-(ethylsulfonamido)-3-oxoprop-1-yn-1-yl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide

1,1′-Carbonyldiimidazole (20 mg) was added with stirring to aheterogeneous solution of 6 (50 mg) in THF (4 mL) and stirred overnightat room temperature.

In another round bottom flask, NaH (15 mg) was added portion-wise to anice cooled solution of ethanesulfonamide (50 mg) in THF (2 mL). Afterthe addition of NaH was complete, the cooling bath was removed and thereaction mixture was stirred at RT for 1 h. This sulfonamide anion wasthen added to the flask containing the activated ester of 6 drop-wise.The resulting reaction mixture was stirred overnight at RT and thevolatiles were removed under reduced pressure. The residue was purifiedby chromatography over silica gel (eluent: 0-8.5% MeOH indichloromethane). 10 mg of 8 was obtained as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer) δ 1.18-1.28 (m, 5H),1.95-2.17 (m, 1H), 2.45 (s, 3H), 2.42-2.48 (m, 1H), 3.87-3.99 (m, 1H),4.09-4.18 (m, 1H), 4.26 (dd, J=10, 5.6 Hz, 1H), 4.34-4.51 (m, 2H), 5.22(d, J=17.2 Hz, 1H), 5.43 (d, J=17.2 Hz, 1H), 5.51 (d, J=52.4 Hz, 1H),6.97 (t, J=4.8 Hz, 1H), 7.22 (t, J=7.2 Hz, 1H), 7.39-7.48 (m, 2H), 7.55(d, J=8 Hz, 1H), 8.35 (s, 1H), 8.45 (brs, 1H), 8.59 (t, J=6 Hz, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆, 300 K): (major rotamer) δ −121.7, −176.1. LC(method 1): t_(R)=1.73 min. LC/MS (EI) m/z: [M+H]⁺ calcd forC₂₉H₇₂ClF₂N₄₀₆S, 633; found 633.

Compound 9:(2S,4R)-1-(2-(3-Acetyl-5-(pyrimidin-2-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide

To a solution of(2S,4R)-1-(2-(3-Acetyl-5-((trimethylsilyl)ethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(6f, synthesized as described for compound 6, in scheme 3) (0.5 g) inTHF (5 mL) was added 1.5 mL of 1.0 M tetrabutylammonium fluoride in THFat RT. The reaction mixture was stirred for 1 h. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography over silica gel (eluent: 0-2% MeOH in CH₂Cl₂) to give0.26 g of (2S,4R)-1-(2-(3-acetyl-5-ethynyl-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(9a) as a light yellow solid.

A mixture of 0.16 g of 2-bromopyrimidine, 0.141 g of PdCl₂(PPh₃)₂, 0.043g of cuprous iodide in DMF (4 mL) was deoxygenated by bubbling argon ina pressure vessel. Triethylamine (2.0 mL) and 0.250 g of(2S,4R)-1-(2-(3-Acetyl-5-ethynyl-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(9a) were added under argon. The pressure vessel was capped and heatedat 90° C. overnight. Then the reaction mixture was cooled to RT and thesolvent was removed under reduced pressure. The residue was purified bycolumn chromatography over silica gel (eluent: 0-4.5% MeOH in CH₂Cl₂) togive 35 mg of the desired product(2S,4R)-1-(2-(3-Acetyl-5-(pyrimidin-2-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(9) as a light orange solid. ¹H NMR (400 MHz, DMSO-d₆, 300 K): (majorrotamer) 31.99-2.18 (m, 1H), 2.46 (s, 3H), 3.92 (ddd, J=24.4, 12.4, 2.8Hz, 1H), 4.26 (dd, J=12.8, 20.8 Hz, 1H), 4.32 (dd, J=28.4, 6.0 Hz, 1H),4.39-4.49 (m, 2H), 5.24 (d, J=17.2 Hz, 1H), 5.45 (d, J=17.2 Hz, 1H),5.51 (d, J=52.8 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 7.23 (t, J=6.4 Hz, 1H),7.40-7.51 (m, 4H), 7.59 (d, J=8.4 Hz, 1H), 8.36 (s, 1H), 8.47 (d, J=0.8Hz, 1H), 8.61 (t, J=5.6 Hz, 1H), 8.85 (d, J=4.8 Hz, 2H). ³¹F NMR (376MHz, DMSO-d₆, 300 K): (major rotamer) 3-121.7, −176.1. LC (method 1):t_(R)=1.74 min. LC/MS (EI) m/z: [M+H]⁺ calcd for C₃₀H₂₄ClF₂N₅O₃, 576;found, 576.

Compound 10:(2S,4R)-1-(2-(3-acetyl-6-(3-(ethylsulfonamido)-3-oxoprop-1-yn-1-yl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide

Compound 10 was synthesized using the procedure similar to the synthesisof compound 8. Thus, 100 mg of 2 in DMF was coupled with 93 mg ofethanesulfonamide using 45 mg of 1,1′-carbonyldiimidazole and 37 mg ofNaH. The reaction mixture was poured into 50 mL of water and acidifiedwith 2N aq. HCl. The separated solid was isolated by filtration, washedsuccessively with water and tert-butylmethyl ether. The solid was driedunder high vacuum to yield 11 mg of 10 as brown solid.

¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer) δ 1.11-1.22 (m, 5H),2.01-2.19 (m, 1H), 2.45 (s, 3H), 2.48-2.51 (m, 1H), 3.86-3.98 (m, 1H),4.09-4.17 (m, 1H), 4.26 (dd, J=10, 6 Hz, 1H), 4.34-4.49 (m, 2H), 5.25(d, J=17.2 Hz, 1H), 5.44 (d, J=17.2 Hz, 1H), 5.51 (d, J=53.2 Hz, 1H),6.95 (t, J=8 Hz, 1H), 7.21 (t, J=6 Hz, 1H), 7.38-7.43 (m, 2H), 7.91 (s,1H), 8.25 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 8.61 (t, J=5.6 Hz, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆, 300 K): (major rotamer) δ −121.8, −176.0. LC(method 1): t_(R)=1.73 min. LC/MS (EI) m/z: [M+H]⁺ calcd forC₂₉H₂₇ClF₂N₄O₆S, 633; found 633.

Compound 22:1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide

Compound 22b was prepared using the procedure similar to the synthesisof 6c. Thus, 23.5 g of 22a was coupled with 17.3 mL of tert-butylbromoacetate using 32.5 g of potassium carbonate in 470 mL ofacetonitrile at 90° C. for 3 h. Then the solvent was removed and waterwas added to the residue. The product was isolated by filtration, washedwith water and dried. Finally, the product was washed with 2:1 mixtureof tert-butylmethyl ether and heptane to get 29 g of 22b.

Compound 22c was prepared following similar procedure to the synthesisof 6f. 7.0 g of 22b was coupled with 28 mL of trimethylsilylacetyleneusing 4.69 g of Pd(PPh₃)₄, 1.5 g of cuprous iodide and 28 mL oftriethylamine in 70 mL of DMF at 100° C. overnight. After removal of thesolvent, the crude product was purified by column chromatography oversilica gel (eluent: 0-1% MeOH in dichloromethane) to get 15 g of 22c.

Compound 22d was synthesized following the same procedure as for thesynthesis of 9a. So, 1.6 g of 22c was deprotected using 3.0 mL of 1.0 MTBAF in THF at 0° C. for 15 min. Crude product was purified bychromatography over silica gel (eluent: 0-2.5% MeOH in dichloromethane)to get 1.09 g of 22d as cream-colored solid.

A mixture of 0.31 g of 2-bromopyrimidine, 0.282 g of PdCl₂(PPh₃)₂, 0.086g of cuprous iodide in DMF (4 mL) was deoxygenated by bubbling argon ina pressure vessel. Triethylamine (1.5 mL) and 0.3 g of 22d were addedunder argon. The pressure vessel was capped and heated at 90° C.overnight. Then the reaction mixture was cooled to RT and the solventwas removed under reduced pressure. The residue was purified by columnchromatography over silica gel (eluent: 0-2% MeOH in CH₂Cl₂) to give0.15 g of the desired product tert-butyl2-(3-carbamoyl-5-(pyrimidin-2-ylethynyl)-1H-indazol-1-yl)acetate (22e)light orange solid.

A solution of 1.81 g of 22e in CH₂Cl₂ (3 mL) and TFA (3 mL) was stirredfor 2 h at RT. Then the volatiles were removed under reduced pressure.The residue2-(3-Carbamoyl-5-(pyrimidin-2-ylethynyl)-1H-indazol-1-yl)acetic acid,22f, was used as such for the next step.

3-Bromo-2-fluoroaniline (22g, 30 g) and 2-chlorophenylboronic acid, 22h(61.75 g), Pd(dppf)Cl₂ (19.25 g) and K₂CO₃ (91 g) were taken in a roundbottom flask kept under argon. 400 mL of dioxane and 100 mL of waterwere added to this mixture. The mixture was bubbled with argon for 5 minand heated with stirring at 100° C. overnight. Then the reaction mixturewas filtered through a Celite® pad and the filtrate was concentratedunder reduced pressure. The residue was purified by chromatography oversilica gel (eluent: 0-0.5% MeOH in CH₂Cl₂) to get a white oil. 300 mL ofsaturated HCl in methanol was added to this oil and the solvent wasevaporated to get 30 g of the hydrochloride salt of 22i as white solid.

To an ice cold solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(2a, 24.64 g) in 600 mL of CH₂Cl₂, Ghosez's reagent (15.4 mL) was addeddrop-wise with stirring. The stirring was continued for 3 h. at sametemperature. Then solid hydrochloride salt of 22i (30 g) was added,followed by 55.2 mL of DIEA (3 equiv.). The cooling bath was removed andthe reaction mixture was stirred overnight at RT. The solvent wasco-evaporated with 30 mL of MeOH. The crude product was purified bychromatography over silica gel (eluent: 10-50% CH₂Cl₂ in hexanes, thendichloromethane) to get 37 g of 22j as white solid.

A solution of 35.6 g of compound 22j in 400 mL of 4.0 N HCl in dioxanewas stirred at RT for 4 h. The thick heterogeneous mixture was thenconcentrated under reduced pressure. The residue was sonicated with 350mL of dichloromethane and filtered and the solid washed with 250 mL ofdichloromethane. The isolated solid was dried under high vacuum to get29.2 g of 22k as white solid.

Compound 22f from above and 1.69 g of 22k were taken in 20 mL of DMF. 4mL of DIEA was added to this reaction mixture and cooled in an ice bath.HATU (2.09 g) was added to this cooled solution. After the addition ofHATU, the cooling bath was removed and the reaction mixture was stirredat RT for 1 h. DMF was removed under reduced pressure and the residuewas purified by chromatography over silica gel (eluent: 0-2.5% MeOH indichloromethane) to get 2.46 g of1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide(22).

¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer) δ 2.08-2.29 (m, 1H),2.55-2.63 (m, 1H), 3.90-4.03 (m, 1H), 4.24 (dd, J=21.6, 12 Hz, 1H), 4.78(t, J=8.4 Hz, 1H), 5.56 (d, J=52.8 Hz, 1H), 5.53 (d, J=17.2 Hz, 1H),5.74 (d, J=17.2 Hz, 1H), 7.07 (t, J=8 Hz, 1H), 7.23 (t, J=8 Hz, 1H),7.37-7.54 (m, 5H), 7.58-7.61 (m, 1H), 7.65 (dd, J=8.8, 1.6 Hz, 1H), 7.77(dd, J=8.8, 0.4 Hz, 1H), 7.79 (brs, 1H), 7.97 (t, J=6.8 Hz, 1H), 8.48(d, J=2.4 Hz, 1H), 8.87 (d, J=4.8 Hz, 2H), 9.99 (s, 1H). ¹⁹F NMR (376MHz, DMSO-d₆, 300 K): (major rotamer) δ −126.6,-175.8. LC (method 1):t_(R)=1.99 min. LC/MS (EI) m/z: [M+H]⁺ calcd for C₃₃H₂₄ClF₂N₇O₃, 640;found 640.

Compound 27:1-(2-((1R,3S,5R)-3-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide

(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (27a) was coupled with 22i using Ghosez's reagent as described insynthesis of 22j (scheme 8). Thus, 0.2 g of 27a was coupled with 0.249 gof hydrochloride salt of 22i using 0.128 mL of Ghosez's reagent to get0.3 g of 27b as colorless solid.

A solution of 0.114 g of 27b in CH₂Cl₂ (1.0 mL) and TFA (1.0 mL) wasstirred for 30 min. Then the volatiles were removed under reducedpressure. The residue, 27c, was used as such for the next step.

Compound 22e (0.05 g) was deprotected using 1 mL of TFA and 1 mL ofCH₂Cl₂ to get 22f as described in scheme 7. This crude 22f was thencoupled with 27c following the procedure similar to the synthesis of 22using 0.121 g of HATU and 0.231 mL of DIEA in 1.5 mL of DMF to get 44 mgof1-(2-((1R,3S,5R)-3-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide(27) as white solid.

¹H NMR (400 MHz, CD₃OD, 300 K): (major rotamer) δ 0.649 (br, 1H),1.09-1.12 (m, 1H), 2.02-2.07 (m, 1H), 2.41-2.58 (m, 2H), 3.69-3.77 (m,1H), 4.65 (dd, J=8.8, 4.8 Hz, 1H), 5.67 (d, J=17.2 Hz, 1H), 5.78 (d,J=17.2 Hz, 1H), 7.09 (t, J=7.2 Hz, 1H), 7.22 (t, J=8 Hz, 1H), 7.30-7.36(m, 3H), 7.41 (t, J=5.2 Hz, 1H), 7.47-7.49 (m, 1H), 7.69 (dd, J=18, 8.8Hz, 2H), 7.97 (t, J=7.6 Hz, 1H), 8.57 (s, 1H), 8.84 (d, J=5.2 Hz, 2H).¹⁹F NMR (376 MHz, CD₃OD, 300 K): (major rotamer) δ −128.8. LC (method1): t_(R)=2.10 min. LC/MS (EI) m/z: [M+H]⁺ calcd for C₃₄H₂₅ClFN₇O₃, 634;found 634.

Compound 28:1-(2-((2S,4R)-2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide:Scheme 11

A mixture of 2.5 g of nitrobromide (28a), 7.21 g ofbis(pinacolato)diboron, 1.24 g of PdCl₂(dppf), 3.35 g of potassiumacetate in dioxane (25 mL) was deoxygenated by bubbling argon in apressure vessel. The pressure vessel was capped and heated at 90° C.overnight. Then the reaction mixture was cooled to RT and the solventwas removed under reduced pressure. The residue was diluted withdichloromethane and water. The organic layer was dried (Na₂SO₄) andconcentrated. The crude product was purified by chromatography oversilica gel (eluent: 20% EtOAc in hexanes) to get 2.94 g of 28c.

Same procedure as for the synthesis of 22i was followed, except that thereaction mixture was heated at 110° C. for 2 days. Thus, 2.8 g of 28cwas coupled with 2.02 g of 2-bromo-2-chloropyridine using 85 mg ofPd(dppf)Cl₂ and 3.63 g of potassium carbonate in dioxane-water.Purification of crude product by chromatography over silica gel gave2.25g of 28d.

Compound 28d (2.25 g) was taken in 1:1 mixture of MeOH-4 N aq. HCl (60mL) and 5.8 g of Zn powder was added to this reaction mixture. Thisheterogeneous reaction mixture was stirred overnight at RT. Finally, thereaction mixture was carefully neutralized with sat. aq. NaHCO₃, thevolatiles were removed under reduced pressure and the residue wasextracted with EtOAc. Then the organic layer was dried (Na₂SO₄) andconcentrated. The crude product was purified by chromatography oversilica gel and the product was dissolved in methanolic HCl and taken todryness to get 2.2 g of 28e.

(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(2a) was coupled with amine 28e using Ghosez's reagent followingprocedure described for synthesis of 22j (scheme 8). Thus, 0.249 g ofcompound 2a was coupled with 0.292 g of amine 28e using 0.145 mL ofGhosez's reagent, after chromatographic purification, to get 0.286 g of28f.

Compound 28f (0.286 g) was deprotected using 3 mL of TFA and 3 mL ofdichloromethane to get 28g. Similarly, 0.240 g of 22e was hydrolyzedusing 3 mL of TFA and 3 mL of dichloromethane to get crude 22f. Finally22f was coupled with 28g as described for the synthesis of 22 using0.298 g of HATU and 1 mL of DIEA in 5 mL of DMF. After the removal ofDMF, the residue was purified by chromatography over silica gel (eluent:0-3% MeOH in dichloromethane) to get 200 mg of1-(2-((2S,4R)-2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide(28).

¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer) δ 2.12-2.29 (m, 1H),2.58-2.63 (m, 1H), 3.90-4.02 (m, 1H), 4.23 (dd, J=21.6, 12.4 Hz, 1H),4.76 (t, J=8 Hz, 1H), 5.53 (d, J=17.6 Hz, 1H), 5.55 (d, J=52.8 Hz, 1H),5.73 (d, J=17.6 Hz, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.25 (t, J=8 Hz, 1H),7.49-7.53 (m, 3H), 7.63 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.78(brs, 1H), 8.08 (d, J=8 Hz, 1H), 8.25 (brs, 1H), 8.46 (s, 1H), 8.64 (d,J=4.8 Hz, 1H), 8.86 (d, J=4.8 Hz, 2H), 10.01 (s, 1H). ¹⁹F NMR (376 MHz,DMSO-d₆, 300 K): (major rotamer) δ −126.9, −175.9. LC (method 1):t_(R)=1.54 min. LC/MS (EI) m/z: [M+H]⁺ calcd for C₃₂H₂₃ClF₂N₈O₃, 641;found 641.

Compound 39:1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide

2-Amino-6-bromopyridine (0.191 g) was coupled with 0.23 g oftrans-fluoroproline 2a using 0.146 mL of Ghosez's reagent in presence of0.522 ml of DIEA following the procedure used for the synthesis of 22j.Crude product was purified by chromatography over silica gel (eluent:0-0.1% MeOH in dichloromethane) to get 0.2 g of 39a as white solid.

0.05 g of 22e and 65 mg of 39a were deprotected following proceduredescribed for compound 22 (schemes 7 and 8). Coupling was done using thesame procedure that was used for the synthesis of 22. Crude product waspurified by chromatography over silica gel (eluent: 0-4% MeOH indichloromethane) gave 50 mg of1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide(39) as cream colored solid.

¹H NMR (400 MHz, CD₃OD, 300 K): (major rotamer) δ 2.16-2.37 (m, 1H),2.68-2.73 (m, 1H), 3.95-4.09 (m, 1H), 4.17-4.30 (m, 1H), 4.76 (t, J=8.4Hz, 1H), 5.49 (d, J=52 Hz, 1H), 5.49 (d, J=17.2 Hz, 1H), 5.64 (d, J=17.2Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.47 (t, J=4.8 Hz, 1H), 7.61 (t, J=8Hz, 1H), 7.71 (s, 2H), 8.08 (d, J=8 Hz, 1H), 8.59 (s, 1H), 8.82 (d,J=4.8 Hz, 1H). ¹⁹F NMR (376 MHz, CD₃OD, 300 K): (major rotamer) δ−178.6. LC (method 1): t_(R)=1.48 min. LC/MS (EI) m/z: [M+]⁺ calcd forC₂₆H₂₀BrFN₈O₃, 591; found 591.

Compound 41:1-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide

1.5 g of 27a was coupled with 1.26 g of 2-amino-6-bromopyridine using961 μL of Ghosez's reagent as described for the synthesis of 22j. Crudeproduct was purified by chromatography over silica gel (eluent: 0-0.1%MeOH in dichloromethane) to get 1.5 g of 41a as a white solid.

Compound 22e (0.05 g) and 56 mg of 41a were deprotected as described forcompound 22 (scheme 7& 8). Coupling was done using the same procedurethat was used for the synthesis of 22. Crude product was purified bychromatography over silica gel (eluent: 0-3% MeOH in dichloromethane) toget 50 mg of1-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide(41) as white solid. ¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer) δ0.76 (brs, 1H), 0.99-1.05 (m, 1H), 1.86-1.92 (m, 1H), 2.07-2.29 (m, 2H),3.80 (br, 1H), 4.45 (dd, J=8.8, 5.2 Hz, 1H), 5.54 (d, J=17.2 Hz, 1H),5.87 (d, J=17.2 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.50-7.53 (m, 2H), 7.68(d, J=9.2 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 8.02(d, J=8 Hz, 1H), 8.46 (s, 1H), 8.85 (d, J=4.8 Hz, 2H), 10.76 (s, 1H). LC(method 1): t_(R)=1.60 min. LC/MS (EI) m/z: [M+]⁺ calcd forC₂₇H₂₁BrFN₈O₃, 585; found 585.

Compound 46:1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-((5-fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3-carboxamide

Procedure similar to the synthesis of 22e was followed. Thus, 0.1 g of22d was coupled with 0.592 g of bromopyrimidine 46a in presence of 77 mgof Pd(PPh₃)₄, 25 mg of CuI and 0.245 mL of TEA in 2 mL of DMF at 90° C.Crude product was purified by chromatography over silica gel (eluent:0-2% MeOH in dichloromethane) to get 0.13 g of 46b as cream coloredsolid.

Compound 46b (31 g) and 37 mg of 39a were deprotected as described forcompound 22 (scheme 7&8). Coupling was done using the same procedurethat was used for the synthesis of 22. Crude product was purified bychromatography over silica gel (eluent: 0-2.5% MeOH in dichloromethane)to get 36 mg of1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-((5-fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3-carboxamide(46) as white solid.

¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer) δ 2.03-2.23 (m, 1H),2.52-2.56 (m 1H), 3.88-4.03 (m, 1H), 4.21 (dd, J=22.4, 12.8 Hz, 1H),4.66 (t, J=8 Hz, 1H), 5.53 (d, J=52.8 Hz, 1H), 5.52 (d, J=17.2 Hz, 1H),5.73 (d, J=17.2 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.53 (s, 1H), 7.66-7.69(m, 1H), 7.72 (d, J=8 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.84 (s, 1H), 8.02(d, J=8 Hz, 1H), 8.45 (s, 1H), 8.96 (d, J=0.8 Hz, 2H), 11.02 (s, 1H).¹⁹F NMR (376 MHz, DMSO-d₆, 300 K): (major rotamer) δ −135.7, −175.7. LC(method 1): t_(R)=1.69 min. LC/MS (EI) m/z: [M+H]⁺ calcd forC₂₆H₁₉BrF₂N₆O₃, 609; found 609.

Compound 49:1-(2-((2S,4R)-2-((2′-chloro-2,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide

Same procedure as for the synthesis of 2c in scheme 1 was followed.Thus, 1.0 g of 3-bromo-2-fluoroaniline was coupled with 1.35 g oftrans-fluoroproline 2a in presence of 2.4 g of HATU in DMF to get 0.695g of 49a.

Prepared following the procedure for the synthesis of 22i (scheme 8).Thus, 0.3 g of 49a was coupled with 0.387 g of boronic acid 49b using0.108 g of Pd(dppf)Cl₂ and 0.512 g of K₂CO₃ in dioxane-water to get 280mg of 49c.

0.150 g of 49c and 0.137 g of 22e were deprotected as described insynthesis of compound 22 (schemes 7, 8). Coupling was done using thesame procedure that was used for the synthesis of 22 to get1-(2-((2S,4R)-2-((2′-Chloro-2,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide(49).

¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer) δ 2.11-2.28 (m, 1H),2.53-2.60 (m, 1H), 3.89-4.02 (m, 1H), 4.23 (dd, J=21.6, 12.8 Hz, 1H),4.77 (t, J=8.4 Hz, 1H), 5.55 (d, J=52.4 Hz, 1H), 5.52 (d, J=17.2 Hz,1H), 5.73 (d, J=17.2 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 7.22 (t, J=8 Hz,1H), 7.42-7.46 (m, 1H), 7.52 (t, J=4.8 Hz, 1H), 7.57-7.66 (m, 4H), 7.76(d, J=9.2 Hz, 1H), 7.78 (s, 1H), 7.97 (t, J=7.6 Hz, 1H), 8.46 (s, 1H),8.86 (d, J=4.8 Hz, 2H), 9.99 (s, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆, 300 K):(major rotamer) δ −111.6, −126.7, −175.9. LC (method 1): t_(R)=2.04 min.LC/MS (EI) m/z: [M+H]⁺ calcd for C₃₃H₂₃ClF₃N₇O₃, 658; found 658.

Compound 64:1-(2-((1R,3S,5R)-3-((2′-chloro-2,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-((5-fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3-carboxamide

The acid 27a was coupled with 3-bromo-2fluoroaniline using Ghosez'sreagent as described for the synthesis of 22j.

Same procedure as for the synthesis of 49c was followed. Thus 0.210 g of64a was coupled with 0.275 g of 49b in presence of 77 mg of Pd(dppf)Cl₂to get 0.184 g of 64b.

Compound 64b (0.136 g) and 0.100 g of 46b were deprotected as describedin synthesis of compound 22 (scheme 7&8). Coupling was done using thesame procedure that was used for the synthesis of 22 to give1-(2-((1R,3S,5R)-3-((2′-Chloro-2,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-((5-fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3-carboxamide(64). ¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer) δ 0.8 (m, 1H),1.01-1.05 (m, 1H), 1.85-1.95 (m, 1H), 2.28-2.31 (m, 2H), 3.79 (t, J=4.8Hz, 1H), 4.54 (t, J=6.4 Hz, 1H), 5.55 (d, J=17.2 Hz, 1H), 5.87 (d,J=17.2 Hz, 1H), 7.08 (t, J=6.8 Hz, 1H), 7.23 (t, J=8 Hz, 1H), 7.31-7.35(m, 1H), 7.45 (t, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.59 (dd, J=8.8, 2.4 Hz,1H), 7.64 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.92(t, J=7.6 Hz, 1H), 8.46 (s, 1H), 8.96 (s, 2H), 9.75 (s, 1H). ¹⁹F NMR(376 MHz, DMSO-d₆, 300 K): (major rotamer) δ −111.6, −126.5, −135.7. LC(method 1): t_(R)=2.56 min. LC/MS (EI) m/z: [M+H]⁺ calcd forC₃₄H₂₃ClF₃N₇O₃, 670; found 670.

Compound 65:1-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-((4-fluoropyridin-2-yl)ethynyl)-1H-indazole-3-carboxamide

Procedure similar to the synthesis of 22e was followed. Thus, 0.1 g of22d was coupled with 0.589 g of 2-bromo-4-fluoropyridine in presence of77 mg of Pd(PPh₃)₄, 25 mg of CuI and 0.245 mL of TEA in 2 mL of DMF at90° C. Crude product was purified by chromatography over silica gel(eluent: 0-1.5% MeOH in dichloromethane) to get 0.12 g of 65a as orangesolid.

0.05 g of 65a and 0.53 g of 41a were deprotected as described insynthesis of compound 22 (scheme 7&8). Coupling was done using the sameprocedure that was used for the synthesis of 22. 53 mg of1-(2-((1R,3S,5R)-3-((6-Bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-((4-fluoropyridin-2-yl)ethynyl)-1H-indazole-3-carboxamide(65) was isolated as white solid.

¹H NMR (400 MHz, DMSO-d₆, 300 K): (major rotamer) δ 0.75 (brm, 1H),0.99-1.02 (m, 1H), 1.87-1.91 (m, 1H), 2.19-2.24 (m, 1H), 2.29-2.35 (m,1H), 3.80 (t, J=4.8 Hz, 1H), 4.45 (dd, J=8.8, 5.2 Hz, 1H), 5.53 (d,J=17.2 Hz, 1H), 5.86 (d, J=17.2 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.36-7.40(m, 1H), 7.49 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.69-7.73 (m, 2H), 7.78(d, J=9.2 Hz, 1H), 7.79 (s, 1H), 8.02 (d, J=8 Hz, 1H), 8.46 (s, 1H),8.64 (dd, J=8.8, 6 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆, 300 K): (majorrotamer) δ −103. LC (method 1): t_(R)=2.41 min. LC/MS (EI) m/z: [M+H]⁺calcd for C₂₈H₂₁BrFN₇O₃, 603; found 603.

Example 11. Non-Limiting Examples of Compounds of Formula I

Table 1 shows illustrative compounds of Formula I with characterizingdata. The assay of Example 12 was used to determine the IC₅₀'s of thecompounds. Other standard factor D inhibition assays are also available.Three ***s are used to denote compounds with an IC₅₀ less than 1micromolar; two **s indicate compound with an IC₅₀ between 1 micromolarand 10 micromolar, and one * denotes compounds with an IC₅₀ greater than10 micromolar.

TABLE 1 RT min Cmp (Method A MS No. Structure Name IC₅₀ or B) (M + 1)  1

(2S,4R)-1-(2-(3-acetyl-6- ethynyl-1H-indol-1- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2- carboxamide *** 1.97 (A) 498  2

3-(3-acetyl-1-(2-((2S,4R)-2- (3-chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-6- yl)propiolic acid ***1.52 (A) 542  3

(2S,4R)-1-(2-(3-acetyl-6- ((trimethylsilyl)ethynyl)-1H-indol-1-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 2.71 (A) 570  4

methyl 3-(3-acetyl-1-(2- ((2S,4R)-2-(3-chloro-2-fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-6- yl)propiolate *** 1.91 (A) 556  5

(2S,4R)-1-(2-(3-acetyl-6- ((4-amino-2-oxo-1,2- dihydropyrimidin-5-yl)ethynyl)-1H-indol-1- yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.02 (A) 607  6

3-(3-acetyl-1-(2-((2S,4R)-2- (3-chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-5- yl)propiolic acid ***1.26 (A) 542  7

(2S,4R)-1-(2-(3-acetyl-5- ((4-amino-2-oxo-1,2- dihydropyrimidin-5-yl)ethynyl)-1H-indol-1- yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.17 (A) 607  8

(2S,4R)-1-(2-(3-acetyl-5-(3- (ethylsulfonamido)-3-oxoprop-1-ynyl)-1H-indol- 1-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.73 (A) 633  9

(2S,4R)-1-(2-(3-acetyl-5- (pyrimidin-2-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.74 (A) 576 10

(2S,4R)-1-(2-(3-acetyl-6-(3- (ethylsulfonamido)-3-oxoprop-1-ynyl)-1H-indol- 1-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.73 (A) 633 11

3-(1-(2-((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-3-(2,2,2-trifluoroacetyl)-1H-indol-6- yl)propiolic acid *** 2.11 (A) 596 12

(2S,4R)-1-(2-(3-acetyl-5- ((2-fluoro-3- (trifluoromethoxy)phenyl)ethynyl)-1H-indol-1- yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide ** 2.83 (A) 676 13

(2S,4R)-1-(2-(3-acetyl-5- ((5-hydroxypyrimidin-2-yl)ethynyl)-1H-indol-1- yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.44 (A) 592 14

(2S,4R)-1-(2-(3-acetyl-5- (phenylethynyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 2.54 (A) 574 15

1-(2-((2S,4R)-2-(3-ethynyl- 2-fluorophenylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide *** 0.91 (A) 453 16

(2S,4R)-1-(2-(3-acetyl-5- (pyrimidin-5-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.84 (A) 576 17

(2S,4R)-1-(2-(3-acetyl-5- (pyridin-4-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropvrrolidine-2-carboxamide *** 1.52 (A) 575 18

(2S,4R)-1-(2-(3-acetyl-5- (isothiazol-4-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 2.18 (A) 581 19

(2S,4R)-1-(2-(3-acetyl-5- (pyridin-2-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.86 (A) 575 20

1-(2-((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.52 (A) 578 21

(1R,3S,5R)-2-(2-(3-acetyl-5- (pyrimidin-2-ylethynyl)-1H-indol-1-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3- carboxamide *** 184 (A) 583 22

1-(2-((2S,4R)-2-(2′-chloro- 2-fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.99 (A) 640 23

1-(2-((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyridin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.66 (A) 577 24

(2S,4R)-1-(2-(3-acetyl-5- ((3-cyano-1H-pyrazol-4-yl)ethynyl)-1H-indol-1- yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.84 (A) 589 25

1-(2-((2S,4R)-2-(3-chloro-2- fluorophenylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.56 (A) 564 26

(2S,4R)-1-(2-(3-acetyl-5- (pyrazin-2-ylethynyl)-1H-indol-1-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.86 (A) 576 27

1-(2-((1R,3S,5R)-3-(2′- chloro-2-fluorobiphenyl-3- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5- (pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide *** 2.10 (A) 634 28

1-(2-((2S,4R)-2-(3-(3- chloropyridin-2-yl)-2- fluorophenylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.54 (A) 641 29

5-((1H-pyrazol-4- yl)ethynyl)-1-(2-((2S,4R)-2- (3-chloro-2-fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-3- carboxamide *** 1.49 (A) 566 30

1-(2-((2S,4R)-2-(3′-chloro- 2-fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 2.10 (A) 640 31

1-(2-((2S,4R)-4-fluoro-2- (2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-2-carbonyl)pyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide * 1.65 (A) 591 32

1-(2-((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-pyrazolo[3,4- c]pyridine-3-carboxamide *** 1.32 (A) 579 33

1-(2-((2S,4R)-4-fluoro-2-(6- (trifluoromethyl)pyridin-2-ylcarbamoyl)pyrrolidin-1- yl)-2-oxoethyl)-5- (pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide *** 1.61 (A) 581 34

1-(2-((1R,3S,5R)-3-(2- fluoro-3- (trifluoromethoxy)phenyl- carbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5- (pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide *** 1.87 (A) 608 35

1-(2-((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyridin-2-yl)ethynyl)-1H-indazole-3-carboxamide *** 1.91 (A) 595 36

5-((6-aminopyridin-2- yl)ethynyl)-1-(2-((2S,4R)-2- (3-chloro-2-fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-3- carboxamide *** 1.27 (A) 592 37

1-(2-((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((6- fluoropyridin-2-yl)ethynyl)-1H-indazole-3-carboxamide *** 1.96 (A) 595 38

1-(2-((2S,4R)-4-fluoro-2-(2- fluoro-3- (trifluoromethoxy)phenyl-carbamoyl)pyrrolidin- 1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.77 (A) 614 39

1-(2-((2S,4R)-2-(6- bromopyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.48 (A) 591 40

1-(2-((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.73 (A) 596 41

1-(2-((1R,3S,5R)-3-(6- bromopyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5- (pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide *** 1.60 (A) 585 42

(2S,4R)-1-(2-(3-acetyl-5- (pyrimidin-2-ylethynyl)-1H-indol-1-yl)acetyl)-N-(6- bromopyridin-2-yl)-4- fluoropyrrolidine-2-carboxamide *** 1.70 (A) 589 43

1-(2-((1R,3S,5R)-3-(6- bromopyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.81 (A) 603 44

1-(2-((2S,4R)-2-(3,3- dimethylcyclohexyl- carbamoyl)-4-fluoropyrrolidin-1-yl)- 2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.69 (A) 546 45

1-(2-((2S,4R)-4-fluoro-2-(2- fluoro-3-methylbut-2-enylcarbamoyl)pyrrolidin-1- yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H- indazole-3-carboxamide *** 1.31 (A) 522 46

1-(2-((2S,4R)-2-(6- bromopyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.69 (A) 609 47

1-(2-((2S,4R)-2-(6-(2- chlorophenyl)pyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.91 (A) 623 48

1-(2-((2S,4R)-2-(6- bromopyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyridin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.60 (A) 590 49

1-(2-((2S,4R)-2-(2′-chloro- 2,4′-difluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 2.04 (A) 658 50

1-(2-((2S,4R)-2-(6-(1H- pyrazol-4-yl)pyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.11 (A) 579 51

1-(2-((1R,3S,5R)-3-(3- chloro-2- fluorobenzylcarbamoyl)-6,6- difluoro-2-azabicyclo[3.2.0]heptan-2- yl)-2-oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H- indazole-3-carboxamide ** 1.79 (A) 622 52

1-(2-((2S,3R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-3-hydroxypyrrolidin-1-yl)-2- oxoethyl)-5-(pyrimidin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.28 (A) 576 53

1-(2-((1R,3S,5R)-3-(2′- chloro-2-fluorobiphenyl-3- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 2.31 (A) 652 54

1-(2-((1R,3S,5R)-3-(6- cyclopropylpyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5- (pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide *** 1.62 (A) 547 55

1-(2-((2S,4R)-2-(2′-chloro- 2-fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 2.20 (A) 658 56

1-(2-((1R,3S,5R)-3-(6- chloropyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5- (pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide *** 1.56 (A) 541 57

1-(2-((1R,3S,5R)-3-(6- cyanopyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5- (pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide *** 1.39 (A) 532 58

1-(2-((1R,3S,5R)-3-(6- bromopyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-((5-fluoropyridin-2-yl)ethynyl)- 1H-indazole-3-carboxamide *** 2.01 (A) 60259

1-(2-((1R,3S,5R)-3-(6- bromopyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-((5-(trifluoromethyl)pyridin-2- yl)ethynyl)-1H-indazole-3- carboxamide ***2.33 (A) 654 60

1-(2-((1R,3S,5R)-3-(6- bromopyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-((5-cyanopyridin-2-yl)ethynyl)- 1H-indazole-3-carboxamide *** 1.93 (A) 60961

1-(2-((1R,3S,5R)-3-(6- bromopyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-((5-(trifluoromethyl)pyrimidin- 2-yl)ethynyl)-1H-indazole- 3-carboxamide ***2.17 (A) 653 62

1-(2-((1R,3S,5R)-3-(6- fluoropyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5- (pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide *** 1.44 (A) 525 63

1-(2-((2S,4R)-2-(2′-chloro- 2,4′,5′-trifluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 2.32 (A) 694 64

1-(2-((1R,3S,5R)-3-(2′- chloro-2,4′- difluorobiphenyl-3- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 2.56 (A) 670 65

1-(2-((1R,3S,5R)-3-(6- bromopyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-((4-fluoropyridin-2-yl)ethynyl)- 1H-indazole-3-carboxamide *** 2.41 (A) 60466

(S)-3-(2-(3-carbamoyl-5- (pyrimidin-2-ylethynyl)-1H-indazol-1-yl)acetyl)-N-(2′- chloro-2-fluorobiphenyl-3-yl)thiazolidine-2- carboxamide *** 2.47 (A) 640 67

1-(2-((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5- (phenylethynyl)-1H-pyrazolo[3,4-c]pyridine-3- carboxamide *** 2.46 (A) 577 68

1-(2-((2S,4R)-2-(5- bromopyridin-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 2.03 (A) 609 69

1-(2-((2S,4R)-4-fluoro-2-(2- fluoro-3-(pyrimidin-5- yl)phenylcarbamoyl)pyrrolidin-1-yl)-2- oxoethyl)-5- (pyrimidin-2-ylethynyl)-1H-indazole-3-carboxamide *** 1.16 (A) 608 70

1-(2-((2S,4R)-4-fluoro-2-(6- (trifluoromethyl)pyrazin-2-ylcarbamoyl)pyrrolidin-1- yl)-2-oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.65 (A) 600 71

1-(2-((2S,4R)-2-(8- chloroquinolin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.94 (A) 615 72

5-((5-fluoropyrimidin-2- yl)ethynyl)-1-(2-oxo-2-((1R,3S,5R)-3-(1-(2,2,2- trifluoroethyl)-1H-pyrazol- 3-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)ethyl)-1H-indazole-3- carboxamide *** 1.54(A) 596 73

1-(2-((2S,4R)-2-(2′-chloro- 2-fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyridazin-3-ylethynyl)-1H-indazole-3- carboxamide *** 1.93 (A) 640 74

1-(2-((2S,4R)-2-(6-chloro-4- (trifluoromethyl)pyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 2.06 (A) 633 75

1-(2-((2S,4R)-2-(6- chloropyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyridazin-3-ylethynyl)-1H-indazole-3- carboxamide *** 1.37 (A) 547 76

1-(2-((2S,4R)-2-(6-chloro-5- (trifluoromethyl)pyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 2.05 (A) 633 77

1-(2-((1R,3S,5R)-3-(6- chloropyridin-2- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5- (pyridazin-3-ylethynyl)-1H-indazole-3-carboxamide *** 1.48 (A) 541 78

1-(2-((2S,4R)-2-(2′-chloro- 2-fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5-fluoro-4- methoxypyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 2.37 (A) 688 79

1-(2-((2S,4R)-2-(2′-chloro- 2-fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyridazin-4-ylethynyl)-1H-indazole-3- carboxamide *** 1.93 (A) 640 80

1-(2-((2S,4R)-2-(6- chloropyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyridazin-4-ylethynyl)-1H-indazole-3- carboxamide *** 1.37 (A) 547 81

1-(2-((2S,4R)-2-(6-chloro-3- fluoropyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.44 (A) 583 82

1-(2-((2S,4R)-2-(6- chloropyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrazin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.53 (A) 547 83

1-(2-((2S,4R)-2-(2′-chloro- 2-fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrazin-2-ylethynyl)-1H-indazole-3- carboxamide *** 2.08 (A) 640 84

1-(2-((2S,4R)-2-(6- bromopyrazin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.52 (A) 611 85

1-(2-((2S,4R)-2-(6-(2- chlorophenyl)pyrazin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.88 (A) 642 86

1-(2-((2S,4R)-2-(6-(2- chloro-6- fluorophenyl)pyrazin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.87 (A) 660 87

1-(2-((2S,4R)-2-(6-(2- chloro-4,5- difluorophenyl)pyrazin-2-ylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5-fluoropyrimidin-2- yl)ethynyl)-1H-indazole-3- carboxamide *** 2.01 (A)678 88

1-(2-((2S,4R)-2-(6- chloropyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- fluoropyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.64 (A) 565 89

1-(2-((2S,4R)-2-(6- bromopyrazin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(pyrazin-2-ylethynyl)-1H-indazole-3- carboxamide *** 1.41 (A) 594 90

(2S,4R)-1-(2-(3-acetyl-5- ((5-fluoropyrimidin-2-yl)ethynyl)-1H-indazol-1- yl)acelyl)-N-(6- bromopyridin-2-yl)-4-fluoropyrrolidine-2- carboxamide *** 2.14 (A) 608 91

1-(2-((2S,4R)-2-(6- bromopyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((5- methylpyrimidin-2-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.68 (A) 605 92

1-(2-((2S,4R)-2-(6- bromopyridin-2- ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-((2- methoxypyrimidin-5-yl)ethynyl)-1H-indazole-3- carboxamide *** 1.83 (A) 623

Example 12. Human Factor D Assay

Human factor D (purified from human serum, Complement Technology, Inc.)at 80 nM final concentration is incubated with test compound at variousconcentrations for 5 minutes at room temperature in 50 mM Tris, 1M NaCl,pH 7.5. A synthetic substrate Z-L-Lys-SBzl and DTNB (Ellman's reagent)are added to final concentrations of 100 μM each. The increase in coloris recorded at OD₄₀₅ nm in a microplate in kinetic mode over 30 minuteswith 30 second time points in a spectrofluorimeter. IC₅₀ values arecalculated by non-linear regression from the percentage of inhibition ofcomplement factor D activity as a function of test compoundconcentration.

Example 13. Hemolysis Assay

The hemolysis assay was previously described by G. Ruiz-Gomez, et al.,J. Med. Chem. (2009) 52: 6042-6052. In the assay red blood cells (RBC),rabbit erythrocyctes (purchased from Complement Technologies), arewashed using GVB Buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025%NaN₃, pH 7.3) plus 10 mM final Mg-EGTA. Cells are used at aconcentration of 1×10⁸ cells/mL. Prior to the hemolysis assay, theoptimum concentration of Normal Human Serum (NHS) needed to achieve 100%lysis of rabbit erythrocytes is determined by titration. NHS (ComplementTechnologies) is incubated with inhibitor for 15 min at 37° C., rabbiterythrocytes in buffer were added and incubated for an additional 30 minat 37° C. Positive control (100% lysis) consists of serum and RBC andnegative control (0% lysis) of Mg-EGTA buffer and RBC only. Samples arecentrifuged at 2000g for 5 min, and supernatants collected. Opticaldensity of the supernatant is monitored at 405 nm using a UV/visiblespectrophotometer. Percentage lysis in each sample is calculatedrelative to positive control (100% lysis).

This specification has been described with reference to embodiments ofthe invention. However, one of ordinary skill in the art appreciatesthat various modifications and changes can be made without departingfrom the scope of the invention as set forth in the claims below.Accordingly, the specification is to be regarded in an illustrativerather than a restrictive sense, and all such modifications are intendedto be included within the scope of invention.

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein: Q¹ isC(R¹R^(1′)); Q² is C(R²R^(2′)); Q³ is C(R³R^(3′)); X¹ is N and X² is CH;R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently chosen fromhydrogen, halogen, and C₁-C₆alkyl; A is:

R⁴ is chosen from —CHO, —CONH₂, C₂-C₆alkanoyl, hydrogen, —SO₂NH₂,—C(CH₂)₂F, —CH(CF₃)NH₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₂alkyl(C₃-C₇cycloalkyl),

R⁵ is selected from hydrogen —CHO, —C(O)NH₂, —C(O)NH(CH₃), andC₂-C₆alkanoyl; R⁹ and R¹⁰ are independently chosen at each occurrencefrom hydrogen, and C₁-C₆alkyl; X¹² is CR¹²; X¹³ is CR¹³; one of R¹² andR¹³ is chosen from R³¹ and the other of R¹² and R¹³ is chosen from R³²:R³¹ is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino,—COOH, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₂-C₆alkenyloxy, —C(O)OR⁹, C₁-C₆thioalkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and —C(NR⁹)NR⁹R¹⁰; R⁹ and R¹⁰are independently chosen at each occurrence from hydrogen andC₁-C₆alkyl; R³² is

R³⁰ is independently chosen at each occurrence from hydrogen,(phenyl)C₀-C₄alkyl, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlychosen from N, O, and S; L is

R¹⁷ is hydrogen; R¹⁸ and R^(18′) are hydrogen; m is 0, 1, 2, or 3; B is—(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); or—(C₀-C₄alkyl)(biphenyl) each of which B is unsubstituted or substitutedwith one or more substituents independently chosen from R³³ and R³⁴, and0 or 1 substituents chosen from R³⁶; R³³ is independently chosen fromhalogen, hydroxyl, —COOH, cyano, C₁-C₆alkyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,—C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; R³⁴ isindependently chosen from nitro, C₂-C₆alkenyl, C₂-C₆alkynyl, andC₁-C₆thioalkyl; and R³⁶ is independently chosen from (phenyl)C₀-C₂alkyl,(phenyl)C₁-C₂alkoxy, phenoxy, and 6-membered heteroaryl containing 1, 2,or 3 heteroatoms independently chosen from N, O, B, and S, each of whichR³⁶ is unsubstituted or substituted with one or more substituentsindependently chosen from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.
 2. The compound of claim 1, wherein the

ring is selected from:


3. The compound of claim 1, wherein R⁵ is hydrogen.
 4. The compound ofclaim 1, wherein R⁴ is chosen from —CHO, —CONH₂, and C₂-C₆alkanoyl. 5.The compound of claim 4, wherein R³¹ is hydrogen.
 6. The compound ofclaim 5, wherein m is 0 or
 1. 7. The compound of claim 1, wherein B isselected from:


8. The compound of claim 1, wherein B is —(CH₂)(aryl) substituted withtwo substituents independently chosen from R³³ and R³⁴.
 9. The compoundof claim 8, wherein R³³ is halogen.
 10. The compound of claim 9, whereinthere are two R³³ substituents and one is chlorine and the other isfluorine.
 11. The compound of claim 1, wherein B is aryl or heteroaryleach of which B is unsubstituted or substituted with one or moresubstituents independently chosen from R³³ and R³⁴.